Doorn, P.A. van

ANO5 mutations in the Dutch limb girdle muscular dystrophy population (Article)

2013-04-22T00:00:00Z

A Dutch cohort of 105 limb girdle muscular dystrophy (LGMD) patients were subject to subsequent genetic investigations. In half the families a causative mutation was found. Recently mutations were identified in ANO5 causing LGMD2L and Miyoshi-like myopathy (MMD3), but could also be found in patients with hyperCKemia only. Therefore, we analysed the index cases of the remaining 31 as yet undiagnosed families from our previously described cohort of LGMD patients for the presence of ANO5 mutations. Detailed history and neurological examination were available for all patients. Serum creatine kinase (CK) activity, skeletal muscle computed tomography (CT) and cardiological investigations were performed. Mutations in ANO5 were found in 16% of the families: 11 index patients and two sibs, eight males and five females. The founder mutation c.191dupA was present in 8 out of 13 patients. Ten different pathogenic mutations were identified of which seven were novel: five missense and two splice site mutations. The age of these patients ranged from 26 to 69 years and the age of onset varied from 21 to 57 years. Symptoms at onset were related to proximal leg weakness. The weakness was slowly progressive. Calf hypertrophy was present in three patients. Males were more severely affected than females. Serum CK activity was highly elevated in the early stage of disease and moderately increased in later stages. Muscle biopsy showed predominantly dystrophic changes. One patient had hypertrophic cardiomyopathy, two others had intraventricular septum thickening.

Enzyme replacement therapy and fatigue in adults with Pompe disease (Article)

2013-04-19T00:00:00Z

Background: Pompe disease is a hereditary metabolic myopathy, for which enzyme replacement therapy (ERT) has been available since 2006. We investigated whether ERT reduces fatigue in adult patients with Pompe disease. Methods: In this prospective international observational survey, we used the Fatigue Severity Scale (FSS) to measure fatigue. Repeated measures ANOVA was used to analyze the data over time. In a subgroup of patients, we also evaluated muscle strength using the Medical Research Council Scale, measured pulmonary function as Forced Vital Capacity, and assessed depression using the Hospital Anxiety and Depression Scale. Results: We followed 163 patients for a median period of 4 years before ERT and for 3 years during ERT. Before ERT, the mean FSS score remained stable at around 5.3 score points; during ERT, scores improved significantly by 0.13 score points per year (p < 0.001). Fatigue decreased mainly in women, in older patients and in those with shorter disease duration. Patients' improvements in fatigue were moderately correlated with the effect of ERT on depression (r 0.55; CI 95% 0.07 to 0.70) but not with the effect of ERT on muscle strength or pulmonary function. Conclusions: Fatigue is a common and disabling problem in patients with early and advanced stages of Pompe disease. Our finding that ERT helps to reduce fatigue is therefore important for this patient population, irrespective of the mechanisms underlying this effect.

The CMAP scan as a tool to monitor disease progression in ALS and PMA (Article)

2013-04-01T00:00:00Z

Amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA) are characterized by a loss of motor units (MUs), reinnervation and, eventually, muscle fibre loss. These three aspects are all reflected in the compound muscle action potential scan (CMAP scan, a high-detail stimulus response curve), which visualizes large MU potentials as 'steps'. We explored changes in the CMAP scan over time, combined the information on steps and CMAP amplitude into a CMAP scan-based progression score (CSPS), and correlated this score with motor unit number estimates (MUNE). Ten patients (three PMA, seven ALS; age 37-77 years) were included. CMAP scan and MUNE measurements were performed five times during a three-month period. Nine patients had additional measurements. The follow-up period was 3-24 months. Results demonstrated that abnormalities in steps preceded a decline in maximum CMAP amplitude during follow-up. Usually, both steps and maximum CMAP amplitude changed between recordings. The correlation between the CSPS and MUNE was-0.80 (p < 0.01). In conclusion, the CMAP scan can be used to visualize and quantify disease progression in a muscle affected by MND. The CSPS is a measure of MU loss that is quick and easy to obtain and that, in contrast to MUNE, has no sample bias.

Muscle fiber-type distribution, fiber-type-specific damage, and the Pompe disease phenotype (Article)

2012-10-11T00:00:00Z

Pompe disease is a lysosomal storage disorder caused by acid α-glucosidase deficiency and characterized by progressive muscle weakness. Enzyme replacement therapy (ERT) has ameliorated patients' perspectives, but reversal of skeletal muscle pathology remains a challenge. We studied pretreatment biopsies of 22 patients with different phenotypes to investigate to what extent fiber-type distribution and fiber-type-specific damage contribute to clinical diversity. Pompe patients have the same fiber-type distribution as healthy persons, but among nonclassic patients with the same GAA mutation (c.-32-13T>G), those with early onset of symptoms tend to have more type 2 muscle fibers than those with late-onset disease. Further, it seemed that the older, more severely affected classic infantile patients and the wheelchair-bound and ventilated nonclassic patients had a greater proportion of type 2x muscle fibers. However, as in other diseases, this may be caused by physical inactivity of those patients.

Multiplet discharges after electrical stimulation: New evidence for distal excitability changes in motor neuron disease (Article)

2012-10-01T00:00:00Z

We hypothesized that action potentials evoked by distal stimulation might trigger ectopic activity (multiplet discharges, MDs). By studying MDs, we investigated the involvement of the axonal part of the peripheral motor neuron in amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA). We performed stimulated high-density surface EMG recordings of the thenar muscles in 10 ALS/PMA patients, five recordings per patient over a three-month period. Furthermore, motor unit number estimates (MUNE) and ALSFRS-R scores were obtained in sessions 1 and 5. MDs were found in all patients, in 21% of the sampled motor units, and in response to 2.4% of the stimulations. The interspike interval range of the MD components was 2.9-6.5 ms, which is compatible only with a distal MD origin. The number of MDs, as percentage of the number of applied stimuli, was correlated with a decline in ALSFRS-R (r = 0.80, p = 0.006) and MUNE (r = 0.72, p = 0.02). In conclusion, MDs can be elicited with electrical stimulation in ALS and PMA patients. Analysis of MD characteristics provides further indications for pathophysiological excitability changes in the most distal part of the motor neuron. MDs are associated with clinical deterioration.

Effect of enzyme therapy and prognostic factors in 69 adults with Pompe disease: An open-label single-center study (Article)

2012-09-28T00:00:00Z

Abstract. Background: Enzyme replacement therapy (ERT) in adults with Pompe disease, a progressive neuromuscular disorder, is of promising but variable efficacy. We investigated whether it alters the course of disease, and also identified potential prognostic factors. Methods. Patients in this open-label single-center study were treated biweekly with 20 mg/kg alglucosidase alfa. Muscle strength, muscle function, and pulmonary function were assessed every 3-6 months and analyzed using repeated-measures ANOVA. Results: Sixty-nine patients (median age 52.1 years) were followed for a median of 23 months. Muscle strength increased after start of ERT (manual muscle testing 1.4 percentage points per year (pp/y); hand-held dynamometry 4.0 pp/y; both p < 0.001). Forced vital capacity (FVC) remained stable when measured in upright, but declined in supine position (-1.1 pp/y; p = 0.03). Muscle function did not improve in all patients (quick motor function test 0.7 pp/y; p = 0.14), but increased significantly in wheelchair-independent patients and those with mild and moderate muscle weakness.Relative to the pre-treatment period (49 patients with 14 months pre-ERT and 22 months ERT median follow-up), ERT affected muscle strength positively (manual muscle testing +3.3 pp/y, p < 0.001 and hand-held dynamometry +7.9 pp/y, p < 0.001). Its effect on upright FVC was +1.8 pp/y (p = 0.08) and on supine FVC +0.8 (p = 0.38). Favorable prognostic factors were female gender for muscle strength, and younger age and better clinical status for supine FVC. Conclusions: We conclude that ERT positively alters the natural course of Pompe disease in adult patients; muscle strength increased and upright FVC stabilized. Functional outcome is probably best when ERT intervention is timely.

First experience with enzyme replacement therapy during pregnancy and lactation in Pompe disease (Article)

2011-12-01T00:00:00Z

Enzyme replacement therapy (ERT) with alglucosidase alfa was registered as a treatment for Pompe disease in 2006. It is as yet unknown whether ERT can be safely applied during pregnancy and lactation.A primiparous 40-year-old woman diagnosed with Pompe disease continued receiving ERT during pregnancy and lactation. Before pregnancy, she had moderate limb-girdle weakness and used nocturnal ventilation. During pregnancy, her clinical condition remained fairly stable until the 25th gestational week. Thereafter she experienced more problems with mobility and respiration. Fetal growth was normal as monitored by regular ultrasound investigations. A healthy boy was born at a gestational age of 37. weeks and 5. days by elective Cesarean section. There were no maternal complications and the child developed normally. One year after delivery the mother's physical condition was similar as prior to her pregnancy. Pharmacokinetic studies following enzyme infusion showed that alglucosidase alfa was secreted into the breast milk. Activity levels in the milk (245. nmol/ml.h) peaked at 2.5. h after the end of the infusion; which was 2. h later than in the plasma (80 μmol/ml.h). Twenty-four hours after start of the infusion, the enzyme activity in the breast milk was back to the pre-infusion level.In this case report, the continuation of treatment with alglucosidase alfa during pregnancy and lactation has been safe for the mother and the child.

Facial-muscle weakness, speech disorders and dysphagia are common in patients with classic infantile Pompe disease treated with enzyme therapy (Article)

2011-10-18T00:00:00Z

Classic infantile Pompe disease is an inherited generalized glycogen storage disorder caused by deficiency of lysosomal acid α-glucosidase. If left untreated, patients die before one year of age. Although enzyme-replacement therapy (ERT) has significantly prolonged lifespan, it has also revealed new aspects of the disease. For up to 11 years, we investigated the frequency and consequences of facial-muscle weakness, speech disorders and dysphagia in long-term survivors. Sequential photographs were used to determine the timing and severity of facial-muscle weakness. Using standardized articulation tests and fibreoptic endoscopic evaluation of swallowing, we investigated speech and swallowing function in a subset of patients. This study included 11 patients with classic infantile Pompe disease. Median age at the start of ERT was 2.4 months (range 0.1-8.3 months), and median age at the end of the study was 4.3 years (range 7.7 months -12.2 years). All patients developed facial-muscle weakness before the age of 15 months. Speech was studied in four patients. Articulation was disordered, with hypernasal resonance and reduced speech intelligibility in all four. Swallowing function was studied in six patients, the most important findings being ineffective swallowing with residues of food (5/6), penetration or aspiration (3/6), and reduced pharyngeal and/or laryngeal sensibility (2/6). We conclude that facial-muscle weakness, speech disorders and dysphagia are common in long-term survivors receiving ERT for classic infantile Pompe disease. To improve speech and reduce the risk for aspiration, early treatment by a speech therapist and regular swallowing assessments are recommended.

Hearing in adults with Pompe disease (Article)

2011-10-14T00:00:00Z

Hearing loss has been recognized as an important cause of morbidity in infants with Pompe disease, a metabolic disorder caused by deficiency of acid α-glucosidase. It is unknown whether hearing is also affected in adult Pompe patients. We have studied the prevalence, severity, and type of hearing loss in 58 adult patients using tympanometry and pure-tone audiometry. Compared to normative data (International Organisation for Standardisation standard 7029), 72% of patients had impaired hearing thresholds at one or more frequencies in at least one ear. All measured frequencies were equally affected. All patients had a sensorineural type of hearing loss, pointing to cochlear or retrocochlear pathology. Categorised according to the standards of the World Health Organisation 21% of patients had a clinically relevant hearing loss (16% slight, 3% moderate, 2% profound). Though this suggests that hearing loss occurs in a considerable number of patients with Pompe disease, this prevalence is similar to that in the general population. Therefore, we conclude that hearing loss is not a specific feature of Pompe disease in adults.

The quick motor function test: a new tool to rate clinical severity and motor function in Pompe patients (Article)

2011-09-13T00:00:00Z

Pompe disease is a lysosomal storage disorder characterized by progressive muscle weakness. With the emergence of new treatment options, psychometrically robust outcome measures are needed to monitor patients' clinical status. We constructed a motor function test that is easy and quick to use. The Quick Motor Function Test (QMFT) was constructed on the basis of the clinical expertise of several physicians involved in the care of Pompe patients; the Gross Motor Function Measure and the IPA/Erasmus MC Pompe survey. The test comprises 16 items. Validity and test reliability were determined in a cohort of 91 Pompe patients (5 to 76 years of age). In addition, responsiveness of the scale to changes in clinical condition over time was examined in a subgroup of 18 patients receiving treatment and 23 untreated patients. Interrater and intrarater reliabilities were good (intraclass correlation coefficients: 0.78 to 0.98 and 0.76 to 0.98). The test correlated strongly with proximal muscle strength assessed by hand held dynamometry and manual muscle testing (rs= 0.81, rs=0.89), and showed significant differences between patient groups with different disease severities. A clinical-empirical exploration to assess responsiveness showed promising results, albeit it should be repeated in a larger group of patients. In conclusion, the Quick Motor Function Test can reliably rate clinical severity and motor function in children and adults with Pompe disease.

Rate of progression and predictive factors for pulmonary outcome in children and adults with Pompe disease (Article)

2011-09-01T00:00:00Z

Respiratory insufficiency is a serious threat to patients with Pompe disease, a neuromuscular disorder caused by lysosomal acid alpha-glucosidase deficiency. Innovative therapeutic options which may stabilize pulmonary function have recently become available. We therefore determined proportion and severity of pulmonary involvement in patients with Pompe disease, the rate of progression of pulmonary dysfunction, and predictive factors for poor respiratory outcome.In a single-center, prospective, cohort study, we measured vital capacity (VC) in sitting and supine positions, as well as maximum inspiratory (MIP) and expiratory (MEP) mouth pressures, and end expiratory CO2in 17 children and 75 adults with Pompe disease (mean age 42.7years, range 5-76years).Seventy-four percent of all patients, including 53% of the children, had some degree of respiratory dysfunction. Thirty-eight percent had obvious diaphragmatic weakness.Males appeared to have more severe pulmonary involvement than females: at a group level, their mean VC was significantly lower than that of females (p < 0.001), they used mechanical ventilation more often than females (p = 0.042) and the decline over the course of the disease was significantly different between males and females (p = 0.003). Apart from male gender, severe skeletal muscle weakness and long disease duration were the most important predictors of poor respiratory status. During follow-up (average 1.6. years, range 0.5-4.2. years), three patients became ventilator dependent. Annually, there were average decreases in VC in upright position of 0.9% points (p = 0.09), VC in supine position of 1.2% points (p = 0.049), MIP of 3.2% points (p = 0.018) and MEP of 3.8% points (p < 0.01).We conclude that pulmonary dysfunction in Pompe disease is much more common than generally thought. Males, patients with severe muscle weakness, and those with advanced disease duration seem most at risk.

Survival and associated factors in 268 adults with Pompe disease prior to treatment with enzyme replacement therapy (Article)

2011-06-03T00:00:00Z

Background: Pompe disease is a rare lysosomal storage disorder characterized by muscle weakness and wasting. The majority of adult patients have slowly progressive disease, which gradually impairs mobility and respiratory function and may lead to wheelchair and ventilator dependency. It is as yet unknown to what extent the disease reduces the life span of these patients. Our objective was to determine the survival of adults with Pompe disease not receiving ERT and to identify prognostic factors associated with survival. Methods. Data of 268 patients were collected in a prospective international observational study conducted between 2002 and 2009. Survival analyses from time of diagnosis and from time of study entry were performed using Kaplan-Meier curves and Cox-proportional-hazards regression. Results: Median age at study entry was 48 years (range 19-79 years). Median survival after diagnosis was 27 years, while median age at diagnosis was 38 years. During follow-up, twenty-three patients died prior to ERT, with a median age at death of 55 (range 23-77 years). Use of wheelchair and/or respiratory support and patients' score on the Rotterdam Handicap Scale (RHS) were identified as prognostic factors for survival. Five-year survival for patients without a wheelchair or respiratory support was 95% compared to 74% in patients who were wheelchair-bound and used respiratory support. In a Dutch subgroup of 99 patients, we compared the observed number of deaths to the expected number of deaths in the age- and sex-matched general population. During a median follow-up of 2.3 years, the number of deaths among the Dutch Pompe patients was higher than the expected number of deaths in the general population. Conclusion: Our study shows for the first time that untreated adults with Pompe disease have a higher mortality than the general population and that their levels of disability and handicap/participation are the most important factors associated with mortality. These results may be of relevance when addressing the effect of ERT or other potential treatment options on survival.

Serum IgG levels as biomarkers for optimizing IVIg therapy in CIDP (Article)

2011-06-01T00:00:00Z

Intravenous immunoglobulin (IVIg) is a proven effective treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Guillain-Barré syndrome (GBS). In GBS, patients show a large variability in serum immunoglobulin G (IgG) levels after standard IVIg treatment and a large increase in serum IgG levels (ÎIgG) was associated with a better outcome. Whether this is also the case in CIDP is not known. In contrast to GBS, most patients with CIDP need regular IVIg treatment for a prolonged period of time but the speed and magnitude of clinical response varies considerably between patients. Some patients with CIDP may need at least two IVIg courses before clinical signs of improvement become clear. At present, this clinical response is the only indicator used to adjust the IVIg dose and interval during maintenance treatment. Biomarkers reflecting disease activity or IVIg pharmacokinetics might be helpful to monitor patients and find the optimal dosage and frequency of IVIg treatment for individual patients. A recent prospective study in CIDP indicated that the increased ÎIgG after standard IVIg dosage during maintenance treatment was relatively constant within individual patients, but differed considerably between patients who were treated with the same stable dosage and interval of IVIg. Further studies are required to determine whether this variation in pharmacokinetics of IVIg is related with clinical recovery and whether IgG levels can be used as biomarkers to monitor and to adjust the optimal IVIg dosage in individual patients with CIDP.

Symptoms of activity-induced weakness in peripheral nervous system disorders (Article)

2011-06-01T00:00:00Z

Activity-induced weakness was reported in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). This was attributed to activity-dependent conduction block (CB) arising in demyelinated axons. It is not known if activity-induced weakness is common, nor if it is specific forMMNand CIDP. We, therefore, carried out an investigation by questionnaire in 64 MMN patients, 52 CIDP patients, 48 progressive spinal muscular atrophy (PSMA) patients, and 30 normal subjects. Subjects were asked if they experienced an increase in weakness when performing 10 common tasks. The percentage of tasks causing activity-induced weakness was higher in the patient groups than in the normal subjects (p < 0.001). The risk of activity-induced weakness exceeding that in normal subjects was sixfold higher for each patient group when adjusted for sex, age, and a fatigue score. With further adjustment for scores of weakness and axon loss, no significant differences were found between the patient groups. In conclusion, activity-induced weakness is frequently reported in MMN and CIDP. It is, however, not specific for these neuropathies as PSMA patients reported it to the same extent.

Screening for antecedent Campylobacter jejuni infections and anti-ganglioside antibodies in idiopathic neuralgic amyotrophy (Article)

2011-06-01T00:00:00Z

Selective Digestive Tract Decontamination Decreases Time on Ventilator in Guillain-Barré Syndrome (Article)

2011-04-06T00:00:00Z

Background: Ventilator-associated pneumonia (VAP) occurs in more than half of mechanically ventilated patients with Guillain-Barré syndrome (GBS) and is associated with prolonged mechanical ventilation (MV). We investigated the impact of selective decontamination of the digestive tract (SDD), an intervention that reduces hospital acquired infections in ICU patients, on duration of MV in GBS and neurological outcome at 6 months. Methods: We performed a retrospective study in mechanically ventilated GBS patients in the Netherlands. We compared patients treated with and without SDD. Main outcomes were duration of MV and the ability to walk independently at 6 months. Statistical comparison was done with logistic and ordinal regression analyses. Results: We included 124 GBS patients on MV at 2 weeks after first symptoms (SDD, n = 54 and non-SDD, n = 70). The median duration of MV without SDD was 42 days (interquartile range, IQR 25-77 days) versus 29 days with SDD (IQR 17-45 days). Median duration of MV for all included patients was 35 days. The adjusted odds ratio (OR) for duration of MV > 35 days in the SDD versus the non-SDD cohort was 0.37 (95% CI 0.17-0.77). SDD did not affect neurological recovery after 6 months from first symptoms. VAP occurred in 12% (95% CI 2-22%) in the SDD cohort and in 47% (95% CI 35-59%) in the non-SDD cohort. Conclusions: SDD in mechanically ventilated GBS patients reduced the time on the ventilator, probably by preventing VAP, but did not affect neurological recovery after 6 months.

Upper and extra-motoneuron involvement in early motoneuron disease: A diffusion tensor imaging study (Article)

2011-04-01T00:00:00Z

Motoneuron disease is a term encompassing three phenotypes defined largely by the balance of upper versus lower motoneuron involvement, namely amyotrophic lateral sclerosis, primary lateral sclerosis and progressive muscular atrophy. However, neuroradiological and pathological findings in these phenotypes suggest that degeneration may exceed the neuronal system upon which clinical diagnosis is based. To further delineate the phenotypes within the motoneuron disease spectrum, this controlled study assessed the upper- and extra-motoneuron white matter involvement in cohorts of patients with motoneuron disease phenotypes shortly after diagnosis by comparing diffusion tensor imaging data of the different cohorts to those of healthy controls and directly between the motoneuron disease phenotypes (n=12 for each cohort). Furthermore, we acquired follow-up data 6 months later to evaluate fractional anisotropy changes over time. Combined use of diffusion tensor tractography of the corticospinal tract and whole-brain voxel-based analysis allowed for comparison of the sensitivity of these techniques to detect white matter involvement in motoneuron disease. The voxel-based analysis demonstrated varying extents of white matter involvement in different phenotypes of motoneuron disease, albeit in quite similar anatomical locations. In general, fractional anisotropy reductions were modest in progressive muscular atrophy and most extensive in primary lateral sclerosis. The most extensive patterns of fractional anisotropy reduction were observed over time in the voxel-based analysis, indicating progressive extra-motor white matter degeneration in limb- and bulbar onset amyotrophic lateral sclerosis and in progressive muscular atrophy. The observation of both upper motor and extra-motoneuron involvement in all phenotypes of motoneuron disease shortly after diagnosis suggests that these are all part of a single spectrum of multisystem neurodegenerative disease. Voxel-based analysis was more sensitive to detect longitudinal changes than diffusion tensor tractography of the corticospinal tract. Voxel-based analyses may be particularly valuable in the evaluation of motor and extra-motor white matter involvement in the early symptomatic stages of motoneuron disease, and for monitoring the spread of pathology over time.

Early recognition of poor prognosis in Guillain-Barré syndrome (Article)

2011-03-15T00:00:00Z

Background: Guillain-Barré syndrome (GBS) has a highly diverse clinical course and outcome, yet patients are treated with a standard therapy. Patients with poor prognosis may benefit from additional treatment, provided they can be identified early, when nerve degeneration is potentially reversible and treatment is most effective. We developed a clinical prognostic model for early prediction of outcome in GBS, applicable for clinical practice and future therapeutic trials. Methods: Data collected prospectively from a derivation cohort of 397 patients with GBS were used to identify risk factors of being unable to walk at 4 weeks, 3 months, and 6 months. Potential predictors of poor outcome (unable to walk unaided) were considered in univariable and multivariable logistic regression models. The clinical model was based on the multivariable logistic regression coefficients of selected predictors and externally validated in an independent cohort of 158 patients with GBS. Results: High age, preceding diarrhea, and low Medical Research Council sumscore at hospital admission and at 1 week were independently associated with being unable to walk at 4 weeks, 3 months, and 6 months (all p 0.05-0.001). The model can be used at hospital admission and at day 7 of admission, the latter having a better predictive ability for the 3 endpoints; the area under the receiver operating characteristic curve (AUC) is 0.84-0.87 and at admission the AUC is 0.73-0.77. The model proved to be valid in the validation cohort. Conclusions: A clinical prediction model applicable early in the course of disease accurately predicts the first 6 months outcome in GBS.

A case of adult Pompe disease presenting with severe fatigue and selective involvement of type 1 muscle fibers (Article)

2011-03-01T00:00:00Z

We present a case of adult Pompe disease (acid maltase deficiency) with an uncommon clinical presentation characterized by severe fatigue and myalgia prior to the onset of limb girdle weakness. Remarkably, the muscle biopsy demonstrated selective involvement of type 1 muscle fibers. The cause and clinical effects of fiber type specific involvement are currently unknown, but the phenomenon might contribute to the clinical heterogeneity in Pompe disease and the variable response to enzyme replacement therapy.

Guillain-Barré syndrome subtypes related to Campylobacter infection (Article)

2011-03-01T00:00:00Z

Background: In Guillain-Barré syndrome (GBS), the diversity in electrophysiological subtypes is unexplained but may be determined by geographical factors and preceding infections. Acute motor axonal neuropathy (AMAN) is a frequent GBS variant in Japan and one study proposed that in Japan, Campylobacter jejuni infections exclusively elicit AMAN. In The Netherlands C jejuni is the predominant type of preceding infection yet AMAN is rare. This may indicate that not all Dutch GBS patients with C jejuni infections have AMAN. Objective: To determine if GBS patients with a preceding C jejuni infection in The Netherlands exclusively have AMAN. Methods: Retrospective analysis of preceding infections in relation to serial electrophysiology and clinical data from 123 GBS patients. C jejuni related cases were defined as having preceding diarrhoea and positive C jejuni serology. Electrophysiological characteristics in C jejuni related cases were compared with those in viral related GBS patients. In addition, eight GBS patients from another cohort with positive stool cultures for C jejuni were analysed. Results: 17 (14%) of 123 patients had C jejuni related GBS. C jejuni patients had lower motor and higher sensory action potentials compared with viral related cases. Nine (53%) C jejuni patients had either AMAN or inexcitable nerves. However, three (18%) patients fulfilled the criteria for acute inflammatory demyelinating polyneuropathy (AIDP). Also, two (25%) of eight additional patients with a C jejuni positive stool sample had AIDP. Conclusion: In The Netherlands, C jejuni infections are strongly, but not exclusively, associated with axonal GBS. Some patients with these infections fulfil current criteria for demyelination.

Revised normative values for grip strength with the Jamar dynamometer (Article)

2011-03-01T00:00:00Z

The Jamar dynamometer has been widely used in various chronic illnesses and has demonstrated its strength as a potential prognostic indicator. Various stratified normative values have been published using different methodologies, leading to conflicting results. No study used statistical techniques considering the non-Gaussian distribution of the obtained grip strength (GS) values. Jamar GS was assessed in 720 healthy participants, subdivided into seven age decade groups consisting of at least 50 men and 50 women each. Normative values (median and fifth values) were calculated using quantile regressions with restricted cubic spline functions on age. Possible confounding personal factors (hand dominance, length, weight, hobby, and job categorization) were examined. Clinically applicable revised normative values for the Jamar dynamometer, stratified for age and gender, are presented. Hand dominance had no influence. Other personal factors only minimally influenced final values. This study provides revised normative GS values for the Jamar dynamometer.

Rasch-built Overall Disability Scale (R-ODS) for immune-mediated peripheral neuropathies (Article)

2011-01-25T00:00:00Z

Objective: To develop a patient-based, linearly weighted scale that captures activity and social participation limitations in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and gammopathy-related polyneuropathy (MGUSP). Methods: A preliminary Rasch-built Overall Disability Scale (R-ODS) containing 146 activity and participation items was constructed, based on the WHO International Classification of Functioning, Disability and Health, literature search, and patient interviews. The preliminary R-ODS was assessed twice (interval: 2-4 weeks; test-retest reliability studies) in 294 patients who experienced GBS in the past (n = 174) or currently have stable CIDP (n = 80) or MGUSP (n = 40). Data were analyzed using the Rasch unidimensional measurement model (RUMM2020). Results: The preliminary R-ODS did not meet the Rasch model expectations. Based on disordered thresholds, misfit statistics, item bias, and local dependency, items were systematically removed to improve the model fit, regularly controlling the class intervals and model statistics. Finally, we succeeded in constructing a 24-item scale that fulfilled all Rasch requirements. "Reading a newspaper/book" and "eating" were the 2 easiest items; "standing for hours" and "running" were the most difficult ones. Good validity and reliability were obtained. Conclusion: The R-ODS is a linearly weighted scale that specifically captures activity and social participation limitations in patients with GBS, CIDP, and MGUSP. Compared to the Overall Disability Sum Score, the R-ODS represents a wider range of item difficulties, thereby better targeting patients with different ability levels. If responsive, the R-ODS will be valuable for future clinical trials and follow-up studies in these conditions. Copyright

Guillain-Barré syndrome subtypes related to Campylobacter infection (Research Paper)

2011-01-01T00:00:00Z

High antibody titer in an adult with Pompe disease affects treatment with alglucosidase alfa (Article)

2010-12-01T00:00:00Z

Clinical trials have demonstrated beneficial effects of enzyme replacement therapy (ERT) with alglucosidase alfa in infants, children and adults with Pompe disease. Recent studies have shown that high antibody titers can occur in patients receiving ERT and counteract the effect of treatment. This particularly occurs in those patients with classic-infantile Pompe disease that do not produce any endogenous acid α-glucosidase (CRIM-negative). It is still unclear to what extent antibody formation affects the outcome of ERT in adults with residual enzyme activity.We present the case of a patient with adult-onset Pompe disease. He was diagnosed at the age of 39. years by enzymatic testing (10.7% residual activity in fibroblasts) and DNA analysis (genotype: c.-32-13T>G/p.Trp516X). Infusion-associated reactions occurred during ERT and the patient's disease progressed. Concurrently, the antibody titer rose to a similarly high level as reported for some CRIM-negative patients with classic-infantile Pompe disease.Using newly developed immunologic-assays we could calculate that approximately 40% of the administered alglucosidase alfa was captured by circulating antibodies. Further, we could demonstrate that uptake of alglucosidase alfa by cultured fibroblasts was inhibited by admixture of the patient's serum.This case demonstrates that also patients with an appreciable amount of properly folded and catalytically active endogenous acid α-glucosidase can develop antibodies against alglucosidase alfa that affect the response to ERT.

Randomised controlled trial comparing two different intravenous immunoglobulins in chronic inflammatory demyelinating polyradiculoneuropathy (Article)

2010-12-01T00:00:00Z

Background: Different preparations of intravenous immunoglobulin (IVIg) are considered to have comparable clinical efficacy but this has never been formally investigated. Some patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) report that some IVIg brands are more effective than others. A liquid IVIg preparation is more user friendly and potentially can be infused at a faster rate. Objectives: The primary objective was to compare the efficacy of two different IVIg brands in CIDP. The secondary objective was to compare their safety. Methods: This was an investigator-initiated multi-centre randomised controlled double-blind trial. Twenty-seven patients with active but stable CIDP treated with their individual stable IVIg (Gammagard S/D) maintenance dose and interval were randomised to receive four infusions of freeze-dried 5% IVIg (Gammagard S/D) or the new liquid 10% IVIg (Kiovig). The overall disability sum score (ODSS) was used as the primary outcome scale. The equivalence margin was defined as a difference of ≤1 point in mean ΔODSS between treatment groups. Main secondary outcome scales were the MRC sum score and the Vigorimeter. Results: Repeated measurements analysis of variance, adjusted for baseline ODSS, showed a clinically insignificant treatment difference of 0.004 (95% CI -0.4 to 0.4). We also found no significant differences in any of the other outcome measures. Besides a lower occurrence of cold shivers in patients randomised to Kiovig (p=0.03), no significant differences were found in the occurrence of adverse events. Conclusions: This trial demonstrated equal clinical efficacy between a freeze-dried and a liquid IVIg preparation for maintenance treatment of CIDP.

Chronic inflammatory demyelinating polyneuropathy disease activity status: Recommendations for clinical research standards and use in clinical practice (Article)

2010-12-01T00:00:00Z

Defining long-term outcomes in chronic inflammatory demyelinating polyneuropathy (CIDP) has been complicated by varying definitions of treatment response and differing scales measuring impairment or disability. An expert panel was convened to devise a CIDP Disease Activity Status (CDAS) and to classify long-term outcome by applying it to 106 patients with a consensus diagnosis of CIDP. Sixty of these cases were graded blindly by three independent reviewers to assess inter-rater reliability. The mean duration of follow-up was 6.4 years (range, 3 months-23 years). Eleven percent of patients were classified as cured (stable examination and off treatment for ≥5 years), 20% were in remission (stable and off treatment for <5 years), 44% had stable active disease but required ongoing therapy for at least 1 year, 7% were improving after recent initiation of therapy, and 18% had unstable active disease (treatment naïve or treatment refractory). Excellent inter-rater reliability was observed (kappa scores: 0.93-0.97; p < 0.0001). The CDAS is considered a simple and reproducible tool to classify patients with CIDP according to disease activity and treatment status that can be applied easily in practice and potentially to select patients for clinical trials.

Pain in Guillain-Barré syndrome: A long-term follow-up study (Article)

2010-10-19T00:00:00Z

Background: Pain in Guillain-Barré syndrome (GBS) may be pronounced and is often overlooked. Objectives: To obtain detailed information about pain in GBS and its clinical variants. Methods: This was a prospective cohort study in 156 patients with GBS (including 18 patients with Miller Fisher syndrome [MFS]). We assessed the location, type, and intensity of pain using questionnaires at standard time points during a 1-year follow-up. Pain data were compared to other clinical features and serology. Results: Pain was reported in the 2 weeks preceding weakness in 36% of patients, 66% reported pain in the acute phase (first 3 weeks after inclusion), and 38% reported pain after 1 year. In the majority of patients, the intensity of pain was moderate to severe. Longitudinal analysis showed high mean pain intensity scores during the entire follow-up. Pain occurred in the whole spectrum of GBS. The mean pain intensity was predominantly high in patients with GBS (non-MFS), patients with sensory disturbances, and severely affected patients. Only during later stages of disease, severity of weakness and disability were significantly correlated with intensity of pain. Conclusions: Pain is a common and often severe symptom in the whole spectrum of GBS (including MFS, mildly affected, and pure motor patients). As it frequently occurs as the first symptom, but may even last for at least 1 year, pain in GBS requires full attention. It is likely that sensory nerve fiber involvement results in more severe pain. Copyright

Electrophysiologic correlations with clinical outcomes in CIDP (Article)

2010-10-01T00:00:00Z

Data are lacking on correlations between changes in nerve conduction (NC) studies and treatment response in chronic inflammatory demyelinating polyneuropathy (CIDP). This report examined data from a randomized, double-blind trial of immune globulin intravenous, 10% caprylate/chromatography purified (IGIV-C [Gamunex]; n = 59) versus placebo (n = 58) every 3 weeks for up to 24 weeks in CIDP. Motor NC results and clinical measures were assessed at baseline and endpoint/week 24. Improvement from baseline in adjusted inflammatory neuropathy cause and treatment score correlated with improvement in proximally evoked compound muscle action potential (CMAP) amplitudes (r = -0.53; P < 0.001) of all nerves tested and with improvement in CMAP amplitude of the most severely affected motor nerve (r = -0.36; P < 0.001). Correlations were observed between improvement in averaged CMAP amplitudes and dominant-hand grip strength (r = 0.44; P < 0.001) and Medical Research Council sum score (r = 0.38; P < 0.001). Overall, the change in electrophysiologic measures of NC in CIDP correlated with clinical response to treatment.

Safety and tolerability of immune globulin intravenous in chronic inflammatory demyelinating polyradiculoneuropathy (Article)

2010-09-01T00:00:00Z

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a common inflammatory neuropathy that can be progressive, stepwise progressive, or relapsing and remitting. Objectives: To further evaluate the long-term safety and tolerability of immune globulin intravenous, 10% caprylate - chromatography purified immune globulin intravenous in CIDP. Design: Randomized multicenter trial. Setting: Hospitals and outpatient clinics. Patients: Adults with CIDP (n=113). Interventions: Immune globulin intravenous, 10% caprylate - chromatography purified (2 g/kg of body weight) or placebo was infused as a baseline loading dose, followed by a maintenance dose (1 g/kg) every 3 weeks for up to 24 weeks. Patients who responded were rerandomized into a double-blind extension phase of immune globulin intravenous, 10% caprylate - chromatography purified (1 g/kg) or placebo every 3 weeks for up to 24 weeks. Patients who relapsed during the extension phase were withdrawn from the study. Main Outcome Measures: Additional analyses of safety and tolerability. Results: Overall, 113 patients and 95 patients were exposed to immune globulin intravenous, 10% caprylate - chromatography purified and placebo, respectively. Exposure to immune globulin intravenous, 10% caprylate - chromatography purified was approximately twice that of placebo (1096 vs 575 infusions). Most maintenance dose courses were administered over 1 day in the immune globulin intravenous, 10% caprylate - chromatography purified (89.1% of 783 dose courses) and placebo (91.1% of 359 dose courses) groups. The most common drug-related adverse events (AEs) with immune globulin intravenous, 10% caprylate - chromatography purified were headache (4.0 per 100 infusions) and pyrexia (2.4 per 100 infusions). Five drug-related serious AEs (pulmonary embolism, pyrexia, vomiting, and 2 headache events) were reported in 3 patients (2.7%) exposed to immune globulin intravenous, 10% caprylate - chromatography purified. The incidence of drug-related serious AEs was higher after loading dose infusions than after maintenance dose infusions (4 AEs vs 1 AE). Age, weight, CIDP severity, and previous immune globulin intravenous exposure had no substantial effect on the percentage of patients with AEs, including serious AEs. Conclusion: Data support a favorable safety and tolerability profile for administration of immune globulin intravenous, 10% caprylate - chromatography purified as CIDP maintenance therapy. Trial Registration: clinicaltrials.gov Identifier NCT00220740.

TLR4-mediated sensing of Campylobacter jejuni by dendritic cells is determined by sialylation (Article)

2010-07-01T00:00:00Z

In Guillain-Barré syndrome (GBS), ganglioside mimicry of Campylobacter jejuni lipo-oligosaccharide (LOS) drives the production of cross-reactive Abs to peripheral nerve gangliosides. We determined whether sialic acid residues in C. jejuni LOS modulate dendritic cell (DC) activation and subsequent B cell proliferation as a possible mechanism for the aberrant humoral immune response in GBS. Highly purified sialylated LOS of C. jejuni isolates from three GBS patients induced human DC maturation and secretion of inflammatory cytokines that were inhibited by anti-TLR4 neutralizing Abs. The extent of TLR4 signaling and DC activation was greater with LOS of the wild type isolates than with nonsialylated LOS of the corresponding sialyltransferase gene knockout (cst-II mutant) strains, indicating that sialylation boosts the DC response to C. jejuni LOS. Supernatants of LOS-activated DCs induced B cell proliferation after cross-linking of surface Igs in the absence of T cells. Lower B cell proliferation indices were found with DC supernatants after DC stimulation with cst-II mutant or neuraminidase desialylated LOS. This study showed that sialylation of C. jejuni LOS enhances human DC activation and subsequent B cell proliferation, which may contribute to the development of cross-reactive anti-ganglioside Abs found in GBS patients following C. jejuni infection. Copyright

Timing and course of clinical response to intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (Article)

2010-07-01T00:00:00Z

Objective: To investigate the timing, course, and clinical characteristics of the response to intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Design: Data were extracted from the ICE trial, a randomized, double-blind, placebo-controlled trial of immune globulin intravenous, 10% caprylate/ chromatography purified (IGIV-C). Setting: Multiple international centers. Participants: One hundred seventeen individuals with CIDP. Intervention: Treatment with IGIV-C (Gamunex, n=59) or placebo (n=58), with IGIV-C administered as a 2-g/kg loading dose followed by a 1-g/kg maintenance dose every 3 weeks, for up to 24 weeks. Main Outcome Measures: The primary efficacy parameter was an improvement of 1 or more points in adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. Participants treated with IGIV-C were divided into subgroups based on meeting responder vs nonresponder definitions and by time to first improvement. Results: Among 30 responders to IGIV-C, 14 (47%) patients had improved adjusted INCAT scores by week 3, and 16 (53%) patients improved at week 6 after a second infusion. Participants who improved by week 3 were more severely disabled at baseline than those who improved at 6 weeks. In patients who improved, the number of individuals reaching maximal improvement continued to increase during maintenance therapy for up to 24 weeks. For patients with first improvement by week 3, the change in dominant-hand grip strength over time tended to parallel the INCAT score. In patients with first improvement by week 6, however, the improvement in dominant-hand grip strength preceded initial improvement in INCAT score. Conclusions: Data suggest that treatment with 2 courses of IGIV-C administered 3 weeks apart may be required for initial improvement, and continued maintenance therapy may be necessary to achieve a maximal therapeutic response. Trial Registration: clinicaltrials.gov Identifier: NCT00220740.

Prediction of respiratory insufficiency in Guillain-Barré syndrome (Article)

2010-06-01T00:00:00Z

Objective: Respiratory insufficiency is a frequent and serious complication of the Guillain-Barré syndrome (GBS). We aimed to develop a simple but accurate model to predict the chance of respiratory insufficiency in the acute stage of the disease based on clinical characteristics available at hospital admission. Methods: Mechanical ventilation (MV) in the first week of admission was used as an indicator of acute stage respiratory insufficiency. Prospectively collected data from a derivation cohort of 397 GBS patients were used to identify predictors of MV. A multivariate logistic regression model was validated in a separate cohort of 191 GBS patients. Model performance criteria comprised discrimination (area under receiver operating curve [AUC]) and calibration (graphically). A scoring system for clinical practice was constructed from the regression coefficients of the model in the combined cohorts. Results: In the derivation cohort, 22% needed MV in the first week of admission. Days between onset of weakness and admission, Medical Research Council sum score, and presence of facial and/or bulbar weakness were the main predictors of MV. The prognostic model had a good discriminative ability (AUC, 0.84). In the validation cohort, 14% needed MV in the first week of admission, and both calibration and discriminative ability of the model were good (AUC, 0.82). The scoring system ranged from 0 to 7, with corresponding chances of respiratory insufficiency from 1 to 91%. Interpretation: This model accurately predicts development of respiratory insufficiency within 1 week in patients with GBS, using clinical characteristics available at admission. After further validation, the model may assist in clinical decision making, for example, on patient transfer to an intensive care unit.

IVIG treatment and prognosis in guillain-barré syndrome (Article)

2010-05-01T00:00:00Z

Introduction Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyneuropathy that often leads to severe weakness. Intravenous immunoglobulin (IVIG) is a proven effective treatment for GBS (class 1 evidence). However, about 25% of patients need artificial ventilation and 20% are still unable to walk unaided after 6 months. Important clinical factors associated with poor outcome are age, presence of preceding diarrhea and the severity of disability in the early course of disease. These clinical factors were combined in a clinical prognostic scoring scale, the Erasmus GBS Outcome Scale (EGOS). Materials and Methods GBS patients being unable to walk unaided are currently treated with a standard single IVIg dose (0.4 g/kg bodyweight for 5 days). A recent retrospective study in 174 GBS patients enrolled in one of our randomized controlled clinical trials showed that patients with a minor increase of serum IgG level after standard single IVIg dose recovered significantly slower. Additionally, fewer patients reached the ability to walk unaided at six months after correction for the known clinical prognostic factors (multivariate analysis; P<0.022). Discussion It is yet unknown why some GBS patients only have a minor increase after standard IVIg treatment. By using the EGOS it is possible to select GBS patients with a poor prognosis. These patients potentially may benefit from a second IVIg dose. Conclusion A standard dose of IVIG is not sufficiently effective in many GBS patients. Whether these patients might benefit from a second IVIg dose needs further investigation.

Pulsed high-dose dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind, randomised, controlled trial (Article)

2010-03-01T00:00:00Z

Background: Pulsed high-dose dexamethasone induced long-lasting remission in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in a pilot study. The PREDICT study aimed to compare remission rates in patients with CIDP treated with high-dose dexamethasone with rates in patients treated with standard oral prednisolone. Methods: In eight neuromuscular centres in the Netherlands and one in the UK, patients aged 18 years or older who had newly diagnosed definite or probable CIDP were randomly assigned to a treatment regimen of either pulsed high-dose dexamethasone or standard oral prednisolone. Randomisation was done with a random number generator. The primary outcome measure was remission at 12 months, defined as improvement of at least three points on the Rivermead mobility index and improvement of at least one point on the inflammatory neuropathy cause and treatment disability scale. Analysis was by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07779236. Findings: Between December, 2003, and December, 2008, 40 patients were treated: 24 received dexamethasone and 16 received prednisolone. At 12 months, 16 patients were in remission: ten in the dexamethasone group and six in the prednisolone group (odds ratio [OR] 1·2, 95% CI 0·3-4·4). Most adverse events were minor and did not differ substantially between treatment groups; however, sleeplessness and Cushing's face occurred more often in the prednisolone group. Interpretation: Pulsed high-dose dexamethasone treatment did not induce remission more often than prednisolone treatment. A substantial proportion of patients were in remission at 12 months in both treatment groups. High-dose dexamethasone could be considered as induction therapy in CIDP, but comparison with intravenous immunoglobulin treatment is needed. Funding: The Prinses Beatrix Fonds (MAR01-0213) and the Department of Neurology, Academic Medical Center.

European federation of neurological societies/peripheral nerve society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - First Revision (Article)

2010-03-01T00:00:00Z

Background: Consensus guidelines on the definition, investigation, and treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been previously published in European Journal of Neurology and Journal of the Peripheral Nervous System. Objectives: To revise these guidelines. Methods: Disease experts, including a representative of patients, considered references retrieved from MEDLINE and Cochrane Systematic Reviews published between August 2004 and July 2009 and prepared statements that were agreed in an iterative fashion. Recommendations: The Task Force agreed on Good Practice Points to define clinical and electrophysiological diagnostic criteria for CIDP with or without concomitant diseases and investigations to be considered. The principal treatment recommendations were: (i) intravenous immunoglobulin (IVIg) (Recommendation Level A) or corticosteroids (Recommendation Level C) should be considered in sensory and motor CIDP; (ii) IVIg should be considered as the initial treatment in pure motor CIDP (Good Practice Point); (iii) if IVIg and corticosteroids are ineffective, plasma exchange (PE) should be considered (Recommendation Level A); (iv) if the response is inadequate or the maintenance doses of the initial treatment are high, combination treatments or adding an immunosuppressant or immunomodulatory drug should be considered (Good Practice Point); (v) symptomatic treatment and multidisciplinary management should be considered (Good Practice Point).

Fatigue in neuromuscular disorders: Focus on Guillain-Barré syndrome and Pompe disease (Article)

2010-03-01T00:00:00Z

Fatigue accounts for an important part of the burden experienced by patients with neuromuscular disorders. Substantial high prevalence rates of fatigue are reported in a wide range of neuromuscular disorders, such as Guillain-Barré syndrome and Pompe disease. Fatigue can be subdivided into experienced fatigue and physiological fatigue. Physiological fatigue in turn can be of central or peripheral origin. Peripheral fatigue is an important contributor to fatigue in neuromuscular disorders, but in reaction to neuromuscular disease fatigue of central origin can be an important protective mechanism to restrict further damage. In most cases, severity of fatigue seems to be related with disease severity, possibly with the exception of fatigue occurring in a monophasic disorder like Guillain-Barré syndrome. Treatment of fatigue in neuromuscular disease starts with symptomatic treatment of the underlying disease. When symptoms of fatigue persist, non-pharmacological interventions, such as exercise and cognitive behavioral therapy, can be initiated.

Pharmacokinetics of intravenous immunoglobulin and outcome in Guillain-Barré syndrome (Article)

2009-12-01T00:00:00Z

Objective: Intravenous immunoglobulin (IVIg) is the first choice treatment for Guillain-Barré syndrome (GBS). All patients initially receive the same arbitrary dose of 2g per kg body weight. Not all patients, however, show a good recovery after this standard dose. IVIg clearance may depend on disease severity and vary between individuals, implying that this dose is suboptimal for some patients. In this study, we determined whether the pharmacokinetics of IVIg is related to outcome in GBS. Methods: We included 174 GBS patients who had previously participated in 2 randomized clinical trials. At entry, all patients were unable to walk unaided and received a standard dose of IVIg. Total IgG levels in serum samples obtained immediately before and 2 weeks after the start of IVIg administration were determined by turbidimetry and related to clinical outcome at 6 months. Results: The increase in serum IgG (ΔIgG) 2 weeks after IVIg treatment varied considerably between patients (mean, 7.8g/L; standard deviation, 5.6g/L). Patients with a low ΔIgG recovered significantly more slowly, and fewer reached the ability to walk unaided at 6 months (log-rank p < 0.001). In multivariate analysis adjusted for other known prognostic factors, a low ΔIgG was independently associated with poor outcome ( p = 0.022). Interpretation: After a standard dose of IVIg treatment, GBS patients show a large variation in pharmacokinetics, which is related to clinical outcome. This may indicate that patients with a small increase in serum IgG level may benefit from a higher dosage or second course of IVIg.

Improving fatigue assessment in immune-mediated neuropathies: The modified Rasch-built fatigue severity scale (Article)

2009-12-01T00:00:00Z

Abstract Fatigue is a major disabling complaint in patients with immune-mediated neuropathies (IN). The 9-item fatigue severity scale (FSS) has been used to assess fatigue in these conditions, despite having limitations due to its classic ordinal construct. The aim was to improve fatigue assessment in IN through evaluation of the FSS using a modern clinimetric approach [Rasch unidimensional measurement model (RUMM2020)]. Included were 192 stable patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUSP). The obtained FSS data were exposed to RUMM2020 model to investigate whether this scale would meet its expectations. Also, reliability and validity studies were performed. The original FSS did not meet the Rasch model expectations, primarily based on two misfitting items, one of these also showing bias towards the factor 'walking independent.' After removing these two items and collapsing the original 7-point Likert options to 4-point response categories for the remaining items, we succeeded in constructing a 7-item Rasch-built scale that fulfilled all requirements of unidimensionality, linearity, and rating scale model. Good reliability and validity were also obtained for the modified FSS scale. In conclusion, a 7-item linearly weighted Rasch-built modified FSS is presented for more proper assessment of fatigue in future studies in patients with immune-mediated neuropathies.

Recurrences, vaccinations and long-term symptoms in GBS and CIDP (Article)

2009-12-01T00:00:00Z

Abstract We determined the frequency of recurrent Guillain-Barré syndrome (GBS), whether vaccinations led to recurrences of GBS or an increase of disability in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and we assessed the prevalence of pain, fatigue and the impact on quality of life after GBS and CIDP. Additionally, we assessed the presence of common auto-immune disorders. Four hundred and sixty-one members of the Dutch society of neuromuscular disorders received a questionnaire. Two hundred and forty-five GBS and seventy-six CIDP patients were included (response rate 70%). Nine patients had a confirmed recurrent GBS, and two patients had experienced both GBS and CIDP. Common auto-immune diseases were reported in 9% of GBS and 5% of CIDP patients. None of the 106 GBS patients who received a flu vaccination (range 1-37 times, total 775 vaccinations) reported a recurrence thereafter. Five out of twenty-four CIDP patients who received a flu vaccination (range 1-17 times) reported an increase in symptoms. Pain or severe fatigue was reported in about 70% of patients after the diagnosis of GBS (median 10 years) or after onset of CIDP (median 6 years), and quality of life was significantly reduced. Flu vaccinations seem relatively safe. GBS and CIDP patients often experience pain, fatigue and a reduced quality of life for many years after the diagnosis.

Interventions for fatigue in peripheral neuropathy (Article)

2009-12-01T00:00:00Z

AChR deficiency due to ε-subunit mutations: Two common mutations in the Netherlands (Article)

2009-10-01T00:00:00Z

Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular transmission. We have identified mutations within the acetylcholine receptor (AChR) ε-subunit gene underlying congenital myasthenic syndromes in nine patients (seven kinships) of Dutch origin. Previously reported mutations ε1369delG and εR311Q were found to be common; ε1369delG was present on at least one allele in seven of the nine patients, and εR311Q in six. Phenotypes ranged from relatively mild ptosis and external ophthalmoplegia to generalized myasthenia. The common occurrence of εR311Q and ε1369delG suggests a possible founder for each of these mutations originating in North Western Europe, possibly in Holland. Knowledge of the ethnic or geographic origin within Europe of AChR deficiency patients can help in targeting genetic screening and it may be possible to provide a rapid genetic diagnosis for patients of Dutch origin by screening first for εR311Q and ε1369delG.

Newer therapeutic options for chronic inflammatory demyelinating polyradiculoneuropathy (Article)

2009-06-18T00:00:00Z

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated disorder with variable symptoms and severity that can be difficult to diagnose. Intravenous immunoglobulin, plasma exchange and corticosteroids have all been proven to be beneficial in randomized controlled trials, although the proof for corticosteroids is less clear. Although these treatments are likely to be similar in efficacy, they differ in terms of their cost, availability and adverse effects. These characteristics should be taken into account when deciding which treatment to offer a patient. If there is no response to the first treatment option, one of the other treatments should be tried. Patients with a pure motor CIDP may deteriorate after corticosteroid treatment.Some patients do not respond or become refractory or intolerant to these conventional treatments. Those who become unresponsive to therapy should be checked again for the appearance of a monoclonal protein or other signs of malignancy. Over the years, small non-randomized studies have reported possible beneficial effects of various immunosuppressive agents. A Cochrane review concluded that currently there is insufficient evidence to decide whether these immunosuppressive drugs are beneficial in CIDP. When giving immunosuppressive drugs, one should be aware that some might even cause demyelinating disease. It is difficult to prove beneficial effects of these newer treatments since they have only been used in small groups of patients, who are refractory to other treatments, and often in combination with other treatments. CIDP patients can deteriorate during or after infections or improve spontaneously, making it more difficult to judge treatment efficacy. Various treatments for CIDP are described such as azathioprine, ciclosporin, cyclophosphamide, interferons, methotrexate, mycophenolate mofetil, rituximab and etanercept. An overview of these newer treatments, their mode of action, adverse effects and potential place in the spectrum of treatments for CIDP based on previous reports and their level of evidence is given.

Effect of glucocorticoid receptor gene polymorphisms in Guillain-Barré syndrome (Article)

2009-06-01T00:00:00Z

Guillain-Barré syndrome (GBS) is a postinfectious immune-mediated polyneuroradiculopathy in which host factors influence disease susceptibility and clinical course. Single-nucleotide polymorphisms (SNPs) in the glucocorticoid receptor (GR) gene influence the sensitivity to glucocorticoids and are related to both microbial colonization and susceptibility to develop auto-immune disease. This genetic variation may therefore also influence the chance to develop GBS. In this study, we genotyped 318 GBS patients and 210 control subjects for five known SNPs in the GR gene. We could distinguish six different GR haplotypes of which two carried the BclI polymorphism: haplotype 1, which consists of the minor allele of BclI in combination with the common variant of TthIIII and haplotype 2, which carries the minor allele of BclI as well as the minor allele of TthIIII. The GR haplotypes were not related to susceptibility to develop GBS. Carriers of haplotype 2 had more frequently preceding diarrhea, serum antibodies to GM1 and GD1a, and more severe muscle weakness at entry. Haplotype 1 carriers had a significantly better prognosis. In conclusion, GR haplotypes are not a susceptibility factor for GBS. However, haplotypes carrying the minor allele of the BclI polymorphism were related to the phenotype and outcome of GBS.

What's new in Guillain-Barré syndrome in 2007-2008? (Article)

2009-06-01T00:00:00Z

The years 2007 and early 2008 have been an exciting time for Guillain-Barré syndrome (GBS) research. Epidemiological studies have shown that the incidence of GBS remains stable at about 2/100,000 per year but that there have been changes in hospitalization use, likely due to the widespread availability of IVIg. Research into mechanisms has shown the importance of single amino acids in Campylobacter jejuni and the importance of ganglioside conformation. In a murine model of anti-ganglioside antibody-mediated neuropathy, Eculizumab was effective in reversing clinical disease and preventing pathology. This suggests trials of Eculizumab in GBS should be considered. Unfortunately, there are no new randomized controlled trials in GBS to report although the unmet need is great.

Electrophysiology in chronic inflammatory demyellnatlng polyneuropathy with IGIV (Article)

2009-04-01T00:00:00Z

Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) received immune globulin intravenous, 10% caprylate/chro-matography purified (IGIV-C, Gamunex; n = 59) or placebo (n = 58) every 3 weeks for up to 24 weeks (first period) in a randomized, double-blind, parallel-group, response-conditional, crossover study. Motor and sensory nerves were assessed at baseline and endpoint/week 24. A nonsignificant trend toward improvement in the proximal amplitude of the most severely affected motor nerve was observed with IGIV-C (0.69 ± 1.86 mV) versus placebo (0.47 ± 2.29 mV), and a greater improvement of 1.08 ± 2.15 mV with IGIV-C versus 0.46 ± 2.03 mV with placebo (P = 0.089) was observed with exclusion of data from Erb's point stimulation. Greater improvements from baseline favoring IGIV-C were observed for 127/142 electrophysiologic parameters. The averaged motor amplitudes from all motor nerves significantly improved with IGIV-C versus placebo [treatment difference, 0.62 mV; 95% confidence interval (CI), 0.05, 1.20; P = 0.035], and conduction block decreased significantly (treatment difference, -5.54%; 95% CI, -10.43, -0.64; P = 0.027), particularly in the lower limbs. Overall, the data suggest that IGIV-C improves electrophysiologic parameters in CIDP.

Individual patients who experienced both Guillain-Barré syndrome and CIDP: Letter to the editor (Article)

2009-03-01T00:00:00Z

Concurrent myopathy in patients with Graves' orbitopathy (Article)

2009-02-01T00:00:00Z

Rate of disease progression during long-term follow-up of patients with late-onset Pompe disease (Article)

2009-02-01T00:00:00Z

To determine the rate of disease progression in patients with late-onset Pompe disease, we collected longitudinal data on pulmonary function and skeletal muscle strength in 16 patients whose symptoms had started in childhood or adulthood. The mean duration of follow-up was 16 years (range 4-29 years). During the follow-up period, eight patients (50%) became wheelchair bound and three (19%) became ventilator dependent. At a group level, pulmonary function deteriorated by 1.6% per year, and proximal muscle weakness progressed gradually. At the individual level, however, the rate and extent of progression varied highly between patients. In two thirds of patients, pulmonary function and muscle strength declined simultaneously and to the same extent. The remaining one third of patients showed a variable, sometimes rapidly progressive course, leading to early respirator or wheelchair dependency. These individual differences, especially in pulmonary dysfunction, indicate the need for regular monitoring every 6-12 months depending on the rate of disease progression.

Recurrent Guillain-Barré syndrome (Article)

2009-01-01T00:00:00Z

Background: Guillain-Barré syndrome (G8S) is generally considered to be monophasic, but recurrences do occur in a presently undefined subgroup of patients. Objectives: To determine which subgroup of patients develops a recurrence and to establish whether preceding infections and neurological symptoms are similar in subsequent episodes. Methods: A recurrence was defined as two or more episodes that fulfilled the NINCDS criteria for GBS, with a minimum time between episodes of 2 months (when fully recovered in between) or 4 months (when only partially recovered). Patients with a treatment-related fluctuation or chronic inflammatory demyelinating polyneuropathy with acute onset were excluded. The clinical characteristics of recurrent GBS patients were compared with those of 476 non-recurrent patients. Results: 32 recurrent GBS patients, who had a total of 81 episodes, were identified. The clinical symptoms in a first episode were similar to the following episodes in individual patients, being GBS or its variant Miller Fisher syndrome (MFS) but never both. While neurological symptoms in subsequent episodes were often similar, the severity of the symptoms and the nature of the preceding infections varied. Recurrent patients (mean age 34.2 years) were younger than non-recurrent patients (mean age 46.9; p = 0.001) and more often had MFS (p = 0.049) or milder symptoms (p = 0.011). Conclusions: Genetic or immunological host factors may play an important role in recurrent GBS, since these patients can develop similar symptoms after different preceding infections. Recurrences occur more frequently in patients under 30, with milder symptoms and in MFS.

Cardiac evaluation in children and adults with Pompe disease sharing the common c.-32-13T>G genotype rarely reveals abnormalities (Article)

2008-12-15T00:00:00Z

Background and objective: Pompe disease is an inherited metabolic disorder caused by deficiency of acid α-glucosidase. All affected neonates have a severe hypertrophic cardiomyopathy, leading to cardiac failure and death within the first year of life. We investigated the presence and extent of cardiac involvement in children and adults with Pompe disease with the common c.-32-13T>G genotype to determine the usefulness of cardiac screening in these patients with relatively 'milder' phenotypes. Methods: Cardiac dimensions and function were evaluated through echocardiography, electrocardiography and Holter monitoring. The total group comprised 68 patients with Pompe disease, of whom 22 patients had disease onset before the age of 18. Results: Two patients (3%) had cardiac abnormalities possibly related to Pompe disease: Electrocardiography showed a Wolff-Parkinson-White pattern in an 8-year-old girl, and one severely affected adult patient had a mild hypertrophic cardiomyopathy. This hypertrophy did not change during treatment with recombinant human α-glucosidase. In addition, four adult patients showed minor cardiac abnormalities which did not exceed the prevalence in the general population and were attributed to advanced age, hypertension or pre-existing cardiac pathology unrelated to Pompe disease. Conclusions: Cardiac involvement is rare in Pompe patients with the common c.-32-13T>G genotype. The younger patients were not more frequently affected than the adults. Electrocardiographic evaluation appears to be appropriate as initial screening tool. Extensive cardiac screening seems indicated only if the electrocardiogram is abnormal or the patient has a history of cardiac disease.

Susceptibility to Guillain-Barré syndrome is not associated with CD1A and CD1E gene polymorphisms (Article)

2008-12-15T00:00:00Z

Immune responses to microbial glycolipids that cross-react to neural epitopes may trigger the Guillain-Barré syndrome (GBS). CD1 molecules are involved in antigen presentation of glycolipids and variation in CD1 genes was recently reported to confer susceptibility to develop GBS. This hypothesis was tested by comparing single nucleotide polymorphisms (SNPs) of CD1A and CD1E in 312 well defined GBS patients and 212 healthy controls. SNPs in CD1A and CD1E were not associated with GBS susceptibility, specific clinical subgroups, anti-ganglioside antibodies, antecedent infections and prognosis. Based on this study, CD1 polymorphisms are not a susceptibility or disease modifying factor in GBS.

Guillain-Barré syndrome - Authors' reply (Article)

2008-12-01T00:00:00Z

Cardiac involvement in adults with Pompe disease (Article)

2008-10-01T00:00:00Z

Background. Glycogen storage disease type II or Pompe disease is a neuromuscular disorder caused by deficiency of lysosomal acid α- glucosidase. Classic infantile Pompe disease results in massive left ventricular (LV) hypertrophy and failure. Although Pompe disease is often included in the differential diagnosis of LV hypertrophy the true frequency of cardiac involvement in adults with Pompe disease is not known. Methods. Forty-six consecutive adult patients (mean age 48 ± 12, 22 men) with Pompe disease were included. Each patient underwent a clinical examination, electrocardiography, and rest and low-dose dobutamine (in 20 patients) two-dimensional echocardiography including contrast and tissue Doppler imaging. Results. All patients had limited exercise tolerance; a rollator walking aid was used in seven patients (15%), a wheelchair in 13 patients (28%), and assisted ventilation in 14 patients (30%). Prior to this study, one patient was known with permanent atrial fibrillation, His-bundle ablation and a VVI pacemaker and another patient was known with fluid retention. The first patient had increased LV end-diastolic diameter, impaired LV ejection fraction, low systolic mitral annular velocities and diastolic dysfunction grade II. The patient with fluid retention was wheelchair bound and dependent on 24-h assisted ventilation and showed right ventricular and LV hypertrophy (septum 16 mm, posterior wall 15 mm). LV hypertrophy was not seen in any of the other patients. One woman of advanced age had isolated low systolic mitral annular velocities. Mean global systolic LV function, including contractile reserve, was not decreased in patients with Pompe disease. Eight patients (17%) had mild diastolic dysfunction grade I, related to hypertension in four and advanced age in seven. Conclusions. In adult patients with Pompe disease without objective signs of cardiac affection by 12-leads electrocardiography or physical examination, echocardiographic screening for LV hypertrophy seems not effective.

How to assess new drugs for neuropathies: Advances in trial design and methodology (Article)

2008-10-01T00:00:00Z

Purpose of review New randomized controlled trials are very much needed to improve the outcome in patients with a variety of peripheral neuropathies. A relatively low incidence of immunemediated neuropathies such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy, and slow progression in diabetic or hereditary neuropathies may hinder a rapid inclusion and may lead to undesirable extended trial duration. Recent findings Some recent randomized controlled trials use modern trial methodology. Identification of prognostic factors, stratification for important variables at randomization, and the selection of appropriate outcome measurements using a modern clinimetric approach may contribute to a more proper randomized controlled trial design for trials that can be conducted within a limited time frame. Summary Modern trial methodology and the appropriate use of outcome measurements may improve the quality and reduce the numbers of patients needed in randomized controlled trials in patients with peripheral neuropathies.

Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome (Article)

2008-10-01T00:00:00Z

Guillain-Barré syndrome (GBS) is an important cause of acute neuromuscular paralysis. Molecular mimicry and a cross-reactive immune response play a crucial part in its pathogenesis, at least in those cases with a preceding Campylobacter jejuni infection and with antibodies to gangliosides. The type of preceding infection and patient-related host factors seem to determine the form and severity of the disease. Intravenous immunoglobulin (IVIg) and plasma exchange are effective treatments in GBS; mainly for practical reasons, IVIg is the preferred treatment. Whether mildly affected patients or patients with Miller Fisher syndrome also benefit from IVIg is unclear. Despite medical treatment, GBS often remains a severe disease; 3-10% of patients die and 20% are still unable to walk after 6 months. In addition, many patients have pain and fatigue that can persist for months or years. Advances in prognostic modelling have resulted in the development of a new and simple prognostic outcome scale that might also help to guide new treatment options, particularly in patients with GBS who have a poor prognosis.

EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases (Article)

2008-09-01T00:00:00Z

Despite high-dose intravenous immunoglobulin (IVIG) is widely used in treatment of a number of immune-mediated neurological diseases, the consensus on its optimal use is insufficient. To define the evidence-based optimal use of IVIG in neurology, the recent papers of high relevance were reviewed and consensus recommendations are given according to EFNS guidance regulations. The efficacy of IVIG has been proven in Guillain-Barré syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multifocal mononeuropathy (level A), acute exacerbations of myasthenia gravis (MG) and short-term treatment of severe MG (level A recommendation), and some paraneoplastic neuropathies (level B). IVIG is recommended as a second-line treatment in combination with prednisone in dermatomyositis (level B) and treatment option in polymyositis (level C). IVIG should be considered as a second or third-line therapy in relapsing-remitting multiple sclerosis, if conventional immunomodulatory therapies are not tolerated (level B), and in relapses during pregnancy or post-partum period (good clinical practice point). IVIG seems to have a favourable effect also in paraneoplastic neurological diseases (level A), stiff-person syndrome (level A), some acute-demyelinating diseases and childhood refractory epilepsy (good practice point).

Revising two-point discrimination assessment in normal aging and in patients with polyneuropathies (Article)

2008-07-01T00:00:00Z

Objectives: To revise the static and dynamic normative values for the two-point discrimination test and to examine its applicability and validity in patients with a polyneuropathy. Methods: Two-point discrimination threshold values were assessed in 427 healthy controls and 99 patients mildly affected by a polyneuropathy. The controls were divided into seven age groups ranging from 20-29, 30-39,..., up to 80 years and older; each group consisted of at least 30 men and 30 women. Two-point discrimination examination took place under standardised conditions on the index finger. Correlation studies were performed between the scores obtained and the values derived from the Weinstein Enhanced Sensory Test (WEST) and the arm grade of the Overall Disability SumScore (ODSS) in the patients' group (validity studies). Finally, the sensitivity to detect patients mildly affected by a polyneuropathy was evaluated for static and dynamic assessments. Results: There was a significant age-dependent increase in the two-point discrimination values. No significant gender difference was found. The dynamic threshold values were lower than the static scores. The two-point discrimination values obtained correlated significantly with the arm grade of the ODSS (static values: r = 0.33, p = 0.04; dynamic values: r = 0.37, p = 0.02) and the scores of the WEST in patients (static values: r = 0.58, p = 0.0001; dynamic values: r = 0.55, p = 0.0002). The sensitivity for the static and dynamic threshold values was 28% and 33%, respectively. Conclusion: This study provides age-related normative two-point discrimination threshold values using a two-point discriminator (an aesthesiometer). This easily applicable instrument could be used as part of a more extensive neurological sensory evaluation.

Eight years experience with enzyme replacement therapy in two children and one adult with Pompe disease (Article)

2008-06-01T00:00:00Z

Pompe disease (type 2 glycogenosis, acid maltase deficiency) is a disorder affecting skeletal and cardiac muscle, caused by deficiency of acid α-glucosidase. In 2006 enzyme therapy with recombinant human α-glucosidase received marketing approval based on studies in infants. Results in older children and adults are awaited. Earlier we reported on the 3-year follow-up data of enzyme therapy in two adolescents and one adult. In the present study these patients were followed for another 5 years. Two severely affected patients, wheelchair and ventilator dependent, who had shown stabilization of pulmonary and muscle function in the first 3 years, maintained this stabilization over the 5-year extension period. In addition patients became more independent in daily life activities and quality of life improved. The third moderately affected patient had shown a remarkable improvement in muscle strength and regained the ability to walk over the first period. He showed further improvement of strength and reached normal values for age during the extension phase. The results indicate that both long-term follow-up and timing of treatment are important topics for future studies.

Extension of the clinical spectrum of Danon disease (Article)

2008-04-01T00:00:00Z

Subclass IgG to motor gangliosides related to infection and clinical course in Guillain-Barré syndrome (Article)

2008-02-01T00:00:00Z

In 176 patients with Guillain-Barré syndrome the subclass and cross-reactivity of serum IgG antibodies to motor gangliosides was related to preceding infections and clinical phenotypes. Two subgroups of patients were identified. Presence of only IgG1 antibodies was related to diarrhea, positive Campylobacter serology, cross-reactive antibodies to C. jejuni lipo-oligosaccharides and poor outcome. In contrast, having both IgG1 and IgG3 antibodies was related to upper respiratory tract infections, cross-reactive antibodies to Haemophilus influenzae lipo-oligosaccharides and better outcome. These findings support a model in which C. jejuni and H. influenzae infections induce two distinct patterns of cross-reactive antibodies with different clinical outcome.

Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial (Article)

2008-02-01T00:00:00Z

Background: Short-term studies suggest that intravenous immunoglobulin might reduce disability caused by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but long-term effects have not been shown. We aimed to establish whether 10% caprylate-chromatography purified immune globulin intravenous (IGIV-C) has short-term and long-term benefit in patients with CIDP. Methods: 117 patients with CIDP who met specific neurophysiological inflammatory neuropathy cause and treatment (INCAT) criteria participated in a randomised, double-blind, placebo-controlled, response-conditional crossover trial. IGIV-C (Gamunex) or placebo was given every 3 weeks for up to 24 weeks in an initial treatment period, and patients who did not show an improvement in INCAT disability score of 1 point or more received the alternate treatment in a crossover period. The primary outcome was the percentage of patients who had maintained an improvement from baseline in adjusted INCAT disability score of 1 point or more through to week 24. Patients who showed an improvement and completed 24 weeks of treatment were eligible to be randomly re-assigned in a blinded 24-week extension phase. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00220740. Findings: During the first period, 32 of 59 (54%) patients treated with IGIV-C and 12 of 58 (21%) patients who received placebo had an improvement in adjusted INCAT disability score that was maintained through to week 24 (treatment difference 33·5%, 95% CI 15·4-51·7; p=0·0002). Improvements from baseline to endpoint were also recorded for grip strength in the dominant hand (treatment difference 10·9 kPa, 4·6-17·2; p=0·0008) and the non-dominant hand (8·6 kPa, 2·6-14·6; p=0·005). Results were similar during the crossover period. During the extension phase, participants who continued to receive IGIV-C had a longer time to relapse than did patients treated with placebo (p=0·011). The incidence of serious adverse events per infusion was 0·8% (9/1096) with IGIV-C versus 1·9% (11/575) with placebo. The most common adverse events with IGIV-C were headache, pyrexia, and hypertension. Interpretation: This study, the largest reported trial of any CIDP treatment, shows the short-term and long-term efficacy and safety of IGIV-C and supports use of IGIV-C as a therapy for CIDP.

Inclusion of the transcervical approach in the video-assisted thoracoscopic extended thymectomy (BATET) for myasthenia gravis: A prospective trial [7] (Article)

2008-01-01T00:00:00Z

Congenital hypomyelinating neuropathy, a long term follow-up study in an affected family (Article)

2008-01-01T00:00:00Z

Congenital hypomyelinating neuropathy is a rare condition characterized by prenatal, neonatal or early infantile onset of hypotonia, paresis and areflexia. Most of the few patients described in literature die within the first years of life. Histopathologically there are no or thin myelin sheaths. Mutations have been described in the following genes, MPZ, EGR2, PMP22, and MTMR2. Here we describe a family with a heterozygous mutation in MPZ, confirmed in two generations.

Pompe Disease: A Continuum of Clinical Phenotypes (Article)

2007-12-18T00:00:00Z

Erratum: Treatment of Guillain-Barré syndrome with mycophenolate mofetil: A pilot study (Journal of Neurology, Neurosurgery and Psychiatry (2007) 78 (1012-1013)) (Article)

2007-12-01T00:00:00Z

Transient hypertrichosis in a patient with Guillain-Barré syndrome [3] (Article)

2007-12-01T00:00:00Z

Genetic polymorphisms of macrophage-mediators in Guillain-Barré syndrome (Article)

2007-10-01T00:00:00Z

Macrophages infiltrate peripheral nerves and may contribute to neural damage in the Guillain-Barré syndrome (GBS). We determined whether single nucleotide polymorphisms (SNP) in genes encoding macrophage-mediators are related to the susceptibility and severity of GBS. The frequencies of SNP in the TNFA, MMP9, IL10, and NOS2a genes did not differ between 263 GBS patients and 210 healthy subjects. The MMP9 C(-1562)T and TNFA C(-863)A SNP were associated with severe weakness and poor outcome, indicating that these SNP may be one of the factors predisposing to a severe form of GBS.

Determination of pain and response to methylprednisolone in Guillain-Barré syndrome (Article)

2007-10-01T00:00:00Z

Pain can be a serious problem in patients with Guillain-Barré syndrome (GBS). Different pain symptoms and the effect of methylprednisolone on pain are evaluated. Methods: GBS patients were recruited from a randomized placebo-controlled study comparing intravenous immunoglobulin (IVIg) + methylprednisolone (500 mg for 5 days) versus IVIg + placebo. Presence and severity of pain were prospectively scored at randomization and after 4 weeks. Efficacy of methylprednisolone was evaluated using endpoints: percentage of patients with pain and percentage of patients improving in pain-severity level. Medical records of the subgroup of patients treated in the Erasmus MC were screened retrospectively for different pain symptoms and course. Pain was scored at different time intervals: within 4 weeks before randomization and 0-2, 2-4, 4-24, 24-52 weeks after randomization. Results: 123 (55%) of 223 patients had pain at randomization. In 70%, pain already started before onset of weakness. Methylprednisolone did not show a positive effect on the presence and reduction of pain. In the subgroup of 39 patients, backache (33%), interscapular (28%), muscle (24%), radicular pain (18%) and painful par-/dysaesthesiae (18%) were most frequently present within the period of 4 weeks before randomization. Twenty-six percent had extreme pain 0-2 weeks after randomization. Most symptoms of pain decreased after this period, but painful par-/dysaesthesiae and muscle pain often remained present during at least 6 months. Conclusions: Pain frequently occurs, often starts before onset of weakness and may cause severe complaints. Especially painful par-/dysaesthesiae and muscle pain may persist for months. Methylprednisolone seems to have no significant effect on the presence and intensity of pain.

Treatment of Guillain-Barré syndrome with mycophenolate mofetil: A pilot study [5] (Article)

2007-09-01T00:00:00Z

Immunotherapy for Guillain-Barré syndrome: A systematic review (Article)

2007-09-01T00:00:00Z

Guillain-Barré syndrome (GBS) is an acute inflammatory disorder of the peripheral nervous system thought to be due to autoimmunity for which immunotherapy is usually prescribed. To provide the best evidence on which to base clinical practice, we systematically reviewed the results of randomized trials of immunotherapy for GBS. We searched the Cochrane Library, MEDLINE and EMBASE in July 2006 and used the methods of the Cochrane Neuromuscular Disease Group to extract and synthesize data. Almost all trials used a 7-point disability grade scale. In four trials with altogether 585 severely affected adult participants, those treated with plasma exchange (PE) improved significantly more on this scale 4 weeks after randomization than those who did not, weighted mean difference (WMD) -0.89 (95% confidence interval (CI) -1.14 to -0.63). In five trials with altogether 582 participants, the improvement on the disability grade scale with intravenous immunoglobulin (IVIg) was very similar to that with PE, WMD -0.02 (95% CI -0.25 to 0.20). There was also no significant difference between IVIg and PE for any of the other outcome measures. In one trial with 148 participants, following PE with IVIg did not produce significant extra benefit. Limited evidence from three open trials in children suggested that IVIg hastens recovery compared with supportive care alone. Corticosteroids were compared with placebo or supportive treatment in six trials with altogether 587 participants. There was significant heterogeneity in the analysis of these trials which could be accounted for by analysing separately four small trials of oral corticosteroids with altogether 120 participants, in which there was significantly less improvement after 4 weeks with corticosteroids than without, WMD -0.82 (95% CI -0.17 to -1.47), and two large trials of intravenous methylprednisolone with altogether 467 participants, in which there was no significant difference between corticosteroids and placebo WMD -0.17 (95% CI 0.06 to -0.39). None of the treatments significantly reduced mortality. Since ∼20% of patients die or have persistent disability despite immunotherapy, more research is needed to identify better treatment regimens and new therapeutic strategies.

Increased aortic stiffness in glycogenosis type 2 (Pompe's disease) (Article)

2007-08-09T00:00:00Z

Background: Pompe's disease, also known as acid maltase deficiency or glycogen storage disease type II, is an autosomal recessive disorder in which deficient activity of the enzyme acid α-glucosidase causes intra-lysosomal accumulation of glycogen in muscle and other tissues. The current study was designed to assess aortic stiffness index (β), as a characteristic of aortic elasticity during transthoracic echocardiography in patients with Pompe's disease. Methods: A total of 17 patients (age 44 ± 8 years, 5 males) with Pompe's disease were studied. Their results were compared to 17 age- and gender-matched controls. In all patients, the ascending aorta was recorded with M-mode echocardiography. β was calculated as ln(SBP/DBP)/[(SD-DD)/DD], where SBP and DBP are the systolic and diastolic blood pressures, SD and DD are the systolic and diastolic aortic diameters, and 'ln' is the natural logarithm. Results: Diastolic aortic diameter was 27.4 ± 2.4 mm in Pompe patients and 25.6 ± 2.7 mm in controls (P < 0.05). Systolic aortic diameters did not differ between the groups (29.4 ± 2.5 mm vs 28.3 ± 2.4 mm, P = ns). Aortic stiffness index (β) was increased in Pompe patients compared to controls (14.6 ± 10.1 vs 5.1 ± 2.6, P < 0.001). Conclusions: The results of this study indicate that aortic stiffness is increased in patients with Pompe's disease. This may be due to glycogen storage in the vessel wall causing reduced vascular elasticity.

Origin of ganglioside complex antibodies in Guillain-Barré syndrome (Article)

2007-08-01T00:00:00Z

The origin of antibodies to ganglioside complexes, as new immunotargets for Guillain-Barré syndrome (GBS), is unknown. This was investigated in 21 GBS patients from which Campylobacter jejuni was isolated. Two of these patients had serum IgG to the GM1/GD1a complex and two other patients had IgG to the GQ1b/GD1a complex. These pairs of patients were clinically distinct. These antibodies all cross-reacted to lipo-oligosaccharides (LOS) from the autologous C. jejuni strain. Previous mass spectrometry studies on these LOS showed the presence of oligosaccharides with a similar structure, further supporting the hypothesis that in these patients LOS induced the ganglioside complex antibodies.

Predictors of respiratory failure in Guillain-Barré syndrome: Commentary (Article)

2007-08-01T00:00:00Z

Contribution of central and peripheral factors to residual fatigue in Guillain-Barré syndrome (Article)

2007-07-01T00:00:00Z

Many patients with Guillain-Barré syndrome (GBS) suffer from severe residual fatigue that has an uncertain basis. We determined the relative contribution of peripheral and central factors during a 2-min fatiguing sustained maximal voluntary contraction (MVC) in 10 neurologically well-recovered GBS patients and 12 age- and sex-matched healthy controls. Physiological fatigue was defined as the decline of voluntary force during an MVC of the biceps brachii. Relative amounts of peripheral fatigue and central activation failure were determined combining voluntary force and force responses to electrical stimulation. Surface electromyography was used to determine muscle-fiber conduction velocity. During the first minute of sustained MVC, peripheral fatigue developed more slowly in patients than in controls. Central fatigue only occurred in patients. The muscle-fiber conduction velocity was higher in patients. The initial MVC, decrease of MVC, initial force response, and initial central activation failure did not significantly differ between the groups. Although peripheral mechanisms cannot be excluded in the pathogenesis of residual fatigue after GBS, these results suggest that central changes are involved. This study thus provides further insight into the factors contributing to residual fatigue in GBS patients.

Multifocal motor neuropathy with abrupt onset and spontaneous recovery [9] (Article)

2007-07-01T00:00:00Z

Fatigue: An important feature of late-onset Pompe disease (Article)

2007-07-01T00:00:00Z

Objective: To investigate the prevalence and severity of fatigue in adult patients with Pompe disease. Methods: The Fatigue Severity Scale (FSS) was assessed in an international population of 225 adults with Pompe disease, a metabolic disorder presenting as a slowly progressive proximal myopathy. The FSS scores were compared to those of healthy controls and the relationship between the level of fatigue and other patient characteristics was investigated. Results: The mean age of the participants was 47 (SD 13) years and the mean disease duration 11 (SD 8) years. 43% used a wheelchair and 46% had respiratory support, 29% needed both. 67% of the participants had a FSS score ≥5, indicating severe fatigue. The mean FSS score was 5.2 (SD 1.5), which was significantly higher than that of healthy controls (p < 0.001). Fatigue was not related to age, sex or disease duration. Patients who used a wheelchair or respiratory support were on average more fatigued than those who did not (p = 0.01). However, of the patients who did not use these aids, 59% also had a FSS score ≥5. FSS scores were highest among patients who reported a high frequency of sleep disorders, but patients who never experienced sleep difficulties were also fatigued (mean FSS score = 4.8). Conclusion: Fatigue is highly prevalent among both mildly and severely affected adult patients with Pompe disease. The FSS appears a useful tool in assessing fatigue in Pompe disease.

Impact of late-onset Pompe disease on participation in daily life activities: Evaluation of the Rotterdam Handicap Scale (Article)

2007-07-01T00:00:00Z

With the recent approval of enzyme replacement therapy for Pompe disease, insight into the social consequences of this disorder becomes even more relevant. The aim of this study was to measure the impact of late-onset Pompe disease on participation in daily life activities and to evaluate the applicability of the Rotterdam Handicap Scale (RHS) for use in Pompe disease. Two hundred fifty-seven adult patients from different countries participated in the study. The mean RHS score was 25.9 ± 6.5 on a scale of 9-36. Individual item scores were lowest for 'domestic tasks indoors', 'domestic tasks outdoors', and 'work/study'. The mean RHS score differed significantly between patients with and without respiratory support (22.9 vs. 28.5, p < 0.001) and patients with and without a wheelchair (20.9 vs. 29.5, p < 0.001). No differences in RHS score were found between countries. The RHS showed good internal consistency and excellent Test-retest reliability. A ceiling effect of 8% was present. We conclude that the RHS seems suitable for this patient population and that Pompe disease has a large impact on the participation in daily life activities, in particular on the ability of patients to fulfil their work or study.

A clinical prognostic scoring system for Guillain-Barré syndrome (Article)

2007-07-01T00:00:00Z

Background: Guillain-Barré syndrome (GBS) is an acute post-infectious immune-mediated peripheral neuropathy with a highly variable clinical course and outcome. We aimed to develop and validate a scoring system based on clinical characteristics in the acute phase of GBS to predict outcome at 6 months. Methods: We studied patients with GBS who were unable to walk independently. A derivation set included 388 patients from two randomised controlled trials and one pilot study. Potential predictors were assessed for their association with the inability to walk independently at 6 months. A simple clinical scoring system was developed on the basis of regression coefficients of predictors in a multivariable logistic regression model. Model performance was quantified with respect to discrimination (area under receiver operating characteristics curve, AUC) and calibration (graphically). We validated our scoring system in a set of 374 patients from another randomised trial. Findings: We included three variables that were predictive of poor outcome at 6 months in our model: age, preceding diarrhoea, and GBS disability score at 2 weeks after entry. Scores ranged from 1 to 7, with three categories for age, two for diarrhoea, and five for GBS disability score at 2 weeks. Predictions corresponding to these prognostic scores ranged from 1% to 83% for the inability to walk independently at 6 months. Predictions agreed well with observed outcome frequencies (adequate calibration) and showed a very good discriminative ability (AUC 0·85) in both data sets. Interpretation: A simple scoring system for patients with GBS, based on three clinical characteristics, accurately predicts outcome at 6 months. The system could be used to counsel individual patients and identify high-risk groups to guide future trials.

Does a carpal tunnel syndrome predict an underlying disease? (Article)

2007-06-01T00:00:00Z

Carpal tunnel syndrome (CTS) may be the presenting symptom of an underlying disease such as diabetes mellitus, hypothyroidism or connective tissue disease (CTD). It was investigated whether additional blood tests (glucose level, thyroid-stimulating hormone level and erythrocyte sedimentation rate) are useful to detect diabetes mellitus, hypothyroidism or CTD in patients with CTS who have not been diagnosed with these diseases before. A group of 516 consecutive patients electromyographically diagnosed with CTS without known diabetes mellitus, hypothyroidism or CTD underwent blood tests and were followed up for incident diabetes mellitus, hypothyroidism or CTD to investigate whether these additional blood tests are useful to detect these diseases in patients with CTS. In our CTS population, only two patients were newly diagnosed with diabetes mellitus, two with hypothyroidism and none with CTD. In general, systematic screening for incident diabetes mellitus, hypothyroidism and CTD through additional blood tests seems to be of little additional value in otherwise typical cases of CTS.

TDP-43 pathology in familial frontotemporal dementia and motor neuron disease without Progranulin mutations (Article)

2007-05-01T00:00:00Z

Frontotemporal dementia is accompanied by motor neuron disease (FTD + MND) in ∼10% of cases. There is accumulating evidence for a clinicopathological overlap between FTD and MND based on observations of familial aggregation and neuropathological findings of ubiquitin-positive neuronal cytoplasmatic inclusions (NCI) in lower motor neurons, hippocampus and neocortex in both conditions. Several familial forms exist with different genetic loci and defects. We investigated the familial aggregation and clinical presentation of FTD + MND cases in a large cohort of 368 FTD patients in the Netherlands. Immunohistochemistry of available brain tissue of deceased patients was investigated using a panel of antibodies including ubiquitin, p62 and TAR DNA-binding protein of 43kDa antibodies. A total of eight patients coming from six families had a family history positive for FTD + MND (mean age at onset 53.2 ± 8.4 years). Five patients presented with behavioural changes and cognitive changes followed by motor neuron disease, whereas symptoms of motor neuron disease were the presenting features in the remaining three patients. Other affected relatives in these families showed dementia/FTD, MND or FTD + MND reflecting the clinical interfamilial variation. No mutations were identified in any of the candidate genes, including Superoxide Dismutase 1, dynactin, angiogenin, Microtubule-Associated Protein Tau, valosin-containing protein and progranulin. Available brain tissue of five patients with familial FTD + MND showed NCI in hippocampus, neocortex and spinal cord in all, and neuronal intranuclear inclusions (NII) in two brains. TDP-43 antibody showed robust staining of neuronal inclusions similar in distribution and morphology to NCI and NII. Additionally, TDP-43 antibody also stained ubiquitin-negative glial inclusions in the basal striatum of one case. In conclusion, there exists considerable clinical variation within families with FTD + MND, which may be determined by other genetic or environmental factors. NII are also found in some cases of familial FTD + MND without Progranulin mutations. The observation of glial TDP-43 positive inclusions in one brain is very interesting, although their pathophysiological significance is yet unknown.

The Dutch neuromuscular database CRAMP (Computer Registry of All Myopathies and Polyneuropathies): Development and preliminary data (Article)

2007-01-01T00:00:00Z

Each of the various neuromuscular diseases is rare. Consequently, solid epidemiological data are not available and it is often difficult to find sufficient patients for studies. For this reason, the Dutch neuromuscular database, CRAMP (Computer Registry of All Myopathies and Polyneuropathies), was developed in 2004 by the Dutch Neuromuscular Research Support Centre, to store information on patient characteristics and diagnoses (based on Rowland and McLeod's classification) in a uniform and easily retrievable manner. Care was taken to preserve data confidentiality. It is envisaged that CRAMP will prove particularly useful for studies in which multicentre collaboration is needed to recruit a sufficiently large number of patients. More than 10,000 patients with neuromuscular diseases (4837 female, 5476 male) have been registered since 2004, half of whom (n = 5059) have peripheral nerve disorders.

Epstein-Barr virus and disease activity in multiple sclerosis (Article)

2005-01-01T00:00:00Z

OBJECTIVES: To study in relapsing-remitting (RR) multiple sclerosis (MS) whether exacerbations and brain activity as measured by magnetic resonance imaging (MRI) are associated with plasma levels of anti-Epstein Barr (EBV) antibodies and EBV DNA. METHODS: This was a prospective study with 73 RR MS patients followed for an average of 1.7 years with frequent neurological examination and blood sampling. Antibodies to various EBV proteins were measured by ELISA and plasma EBV DNA was measured by PCR. RESULTS: All MS patients had IgG antibodies to EBV (viral capsid antigen (VCA) and/or EBV nuclear antigen (EBNA)), irrespective whether samples were taken at stable disease or exacerbation. A significantly elevated percentage of the patients (48%) had antibodies against EBV antigens (early antigen, EA) that indicate active viral replication, compared with the age matched healthy controls (25%). Antibodies against a control herpesvirus, cytomegalovirus, were similar between the two groups. The percentage of EA positive individuals and EA titres did not differ between stable disease or exacerbation. Anti-VCA IgM was positive in three cases, unrelated to disease activity. Using a highly sensitive PCR on 51 samples taken at exacerbation visits, only three patients were found to have one timepoint with viraemia, and this viraemia was unrelated to disease activity. Of special note was the fact that anti-EA seropositive patients remained seropositive during follow up, with stable titres over time. We hypothesised that these patients may constitute a subgroup with higher disease activity, due to the triggering effect of a chronic attempt of the virus to reactivate. The EA positive group did not differ from the EA negative with respect to clinical disease activity or other characteristics. However, in the EA positive group, analysis with gadolinium enhanced MRI indicated more MRI disease activity. CONCLUSIONS: There was no evidence for increased clinical disease activity in the subgroup of MS patients with serological signs of EBV reactivation. However, the observation that chronic EBV reactivation may be associated with increased inflammatory activity as assessed by gadolinium enhanced MRI lesions should be reproduced in a larger and independent dataset.

Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk (Article)

2004-01-01T00:00:00Z

OBJECTIVE: Recent reports warn that the worldwide cell culture capacity is insufficient to fulfill the increasing demand for human protein drugs. Production in milk of transgenic animals is an attractive alternative. Kilogram quantities of product per year can be obtained at relatively low costs, even in small animals such as rabbits. We tested the long-term safety and efficacy of recombinant human -glucosidase (rhAGLU) from rabbit milk for the treatment of the lysosomal storage disorder Pompe disease. The disease occurs with an estimated frequency of 1 in 40,000 and is designated as orphan disease. The classic infantile form leads to death at a median age of 6 to 8 months and is diagnosed by absence of alpha-glucosidase activity and presence of fully deleterious mutations in the alpha-glucosidase gene. Cardiac hypertrophy is characteristically present. Loss of muscle strength prevents infants from achieving developmental milestones such as sitting, standing, and walking. Milder forms of the disease are associated with less severe mutations and partial deficiency of alpha-glucosidase. METHODS: In the beginning of 1999, 4 critically ill patients with infantile Pompe disease (2.5-8 months of age) were enrolled in a single-center open-label study and treated intravenously with rhAGLU in a dose of 15 to 40 mg/kg/week. RESULTS: Genotypes of patients were consistent with the most severe form of Pompe disease. Additional molecular analysis failed to detect processed forms of alpha-glucosidase (95, 76, and 70 kDa) in 3 of the 4 patients and revealed only a trace amount of the 95-kDa biosynthetic intermediate form in the fourth (patient 1). With the more sensitive detection method, 35S-methionine incorporation, we could detect low-level synthesis of -glucosidase in 3 of the 4 patients (patients 1, 2, and 4) with some posttranslation modification from 110 kDa to 95 kDa in 1 of them (patient 1). One patient (patient 3) remained totally deficient with both detection methods (negative for cross-reactive immunologic material [CRIM negative]). The alpha-glucosidase activity in skeletal muscle and fibroblasts of all 4 patients was below the lower limit of detection (<2% of normal). The rhAGLU was tolerated well by the patients during >3 years of treatment. Anti-rhAGLU immunoglobulin G titers initially increased during the first 20 to 48 weeks of therapy but declined thereafter. There was no consistent difference in antibody formation comparing CRIM-negative with CRIM-positive patients. Muscle alpha-glucosidase activity increased from <2% to 10% to 20% of normal in all patients during the first 12 weeks of treatment with 15 to 20 mg/kg/week. For optimizing the effect, the dose was increased to 40 mg/kg/week. This resulted, 12 weeks later, in normal alpha-glucosidase activity levels, which were maintained until the last measurement in week 72. Importantly, all 4 patients, including the patient without any endogenous alpha-glucosidase (CRIM negative), revealed mature 76- and 70-kDa forms of -glucosidase on Western blot. Conversion of the 110-kDa precursor from milk to mature 76/70-kDa alpha-glucosidase provides evidence that the enzyme is targeted to lysosomes, where this proteolytic processing occurs. At baseline, patients had severe glycogen storage in the quadriceps muscle as revealed by strong periodic acid-Schiff--positive staining and lacework patterns in hematoxylin and eosin--stained tissue sections. The muscle pathology correlated at each time point with severity of signs. Periodic acid-Schiff intensity diminished and number of vacuoles increased during the first 12 weeks of treatment. Twelve weeks after dose elevation, we observed signs of muscle regeneration in 3 of the 4 patients. Obvious improvement of muscular architecture was seen only in the patient who learned to walk. Clinical effects were significant. All patients survived beyond the age of 4 years, whereas untreated patients succumb at a median age of 6 to 8 months. The characteristic cardiac hypertrophy present at start of treatment diminished significantly. The left ventricular mass index decreased from 171 to 599 g/m2 (upper limit of normal 86.6 g/m2 for infants from 0 to 1 year) to 70 to 160 g/m2 during 84 weeks of treatment. In addition, we found a significant change of slope for the diastolic thickness of the left ventricular posterior wall against time at t = 0 for each separate patient. Remarkably, the younger patients (patients 1 and 3) showed no significant respiratory problems during the first 2 years of life. One of the younger patients recovered from a life-threatening bronchiolitis at the age of 1 year without sequelae, despite borderline oxygen saturations at inclusion. At the age of 2, however, she became ventilator dependent after surgical removal of an infected Port-A-Cath. She died at the age of 4 years and 3 months suddenly after a short period of intractable fever of >42 degrees C, unstable blood pressure, and coma. The respiratory course of patient 1 remained uneventful. The 2 older patients, who both were hypercapnic (partial pressure of carbon dioxide: 10.6 and 9.8 kPa; normal range: 4.5-6.8 kPa) at start of treatment, became ventilator dependent before the first infusion (patient 2) and after 10 weeks of therapy (patient 4). Patient 4 was gradually weaned from the ventilator after 1 year of high-dose treatment and was eventually completely ventilator-free for 5 days, but this situation could not be maintained. Currently, both patients are completely ventilator dependent. The most remarkable progress in motor function was seen in the younger patients (patients 1 and 3). They achieved motor milestones that are unmet in infantile Pompe disease. Patient 1 learned to crawl (12 months), walk (16 months), squat (18 months), and climb stairs (22 months), and patient 3 learned to sit unsupported. The Alberta Infant Motor Scale score for patients 2, 3, and 4 remained far below p5. Patient 1 followed the p5 of normal. CONCLUSION: Our study shows that a safe and effective medicine can be produced in the milk of mammals and encourages additional development of enzyme replacement therapy for the several forms of Pompe disease. Restoration of skeletal muscle function and prevention of pulmonary insufficiency require dosing in the range of 20 to 40 mg/kg/week. The effect depends on residual muscle function at the start of treatment. Early start of treatment is required.

Self reported stressful life events and exacerbations in multiple sclerosis: prospective study (Article)

2003-01-01T00:00:00Z

OBJECTIVE: To study the relation between self reported stressful life events not related to multiple sclerosis and the occurrence of exacerbations in relapsing-remitting multiple sclerosis. DESIGN: Longitudinal, prospective cohort study. SETTING: Outpatient clinic of department of neurology in the Netherlands. PARTICIPANTS: Patients aged 18-55 with relapsing-remitting multiple sclerosis, who could walk with a cane or better (score of 0-6.0 on the expanded disability status scale), and had had at least two exacerbations in 24 months before inclusion in the study. Patients with other serious conditions were excluded. MAIN OUTCOME MEASURE: The risk of increased disease activity as measured by the occurrence of exacerbations after weeks with stressful events. RESULTS: Seventy out of 73 included patients (96%) reported at least one stressful event. In total, 457 stressful life events were reported that were not related to multiple sclerosis. Average follow up time was 1.4 years. Throughout the study, 134 exacerbations occurred in 56 patients and 136 infections occurred in 57 patients. Cox regression analysis with time dependent variables showed that stress was associated with a doubling of the exacerbation rate (relative risk 2.2, 95% confidence interval 1.2 to 4.0, P = 0.014) during the subsequent four weeks. Infections were associated with a threefold increase in the risk of exacerbation, but this effect was found to be independent of experienced stress. CONCLUSION: Stressful events were associated with increased exacerbations in relapsing-remitting multiple sclerosis. This association was independent of the triggering effect of infections on exacerbations of multiple sclerosis.

Connecting impairment, disability, and handicap in immune mediated polyneuropathies (Article)

2003-01-01T00:00:00Z

BACKGROUND: In the World Health Organisation (WHO) International Classification of Impairments, Disabilities, and Handicaps (ICIDH), it is suggested that various levels of outcome are associated with one another. However, the ICIDH has been criticised on the grounds that it only represents a general, non-specific relation between its entities. OBJECTIVE: To examine the significance of the ICIDH in immune mediated polyneuropathies. METHODS: Four impairment measures (fatigue severity scale, MRC sum score, "INCAT" sensory sum score, grip strength with the Vigorimeter), five disability scales (nine hole peg test, 10 metres walking test, an overall disability sum score (ODSS), Hughes functional grading scale, Rankin scale), and a handicap scale (Rotterdam nine items handicap scale (RIHS9)) were assessed in 113 clinically stable patients (83 with Guillain-Barre syndrome, 22 with chronic inflammatory demyelinating polyneuropathy, eight with a gammopathy related polyneuropathy). Regression analyses with backward and forward stepwise strategies were undertaken to determine the correlation between the various levels of outcome (impairment on disability, impairment on handicap, disability leading to handicap, and impairment plus disability on handicap). RESULTS: Impairment measures explained a substantial part of disability (R(2) = 0.64) and about half of the variance in handicap (R(2) = 0.52). Disability measures showed a stronger association with handicap (R(2) = 0.76). Combining impairment and disability scales accounted for 77% of the variance in handicap (RIHS9) scores. CONCLUSIONS: In contrast to some suggestions, support for the ICIDH model is found in the current study because significant associations were shown between its various levels in patients with immune mediated polyneuropathies. Further studies are required to examine other possible contributors to deficits in daily life and social functioning in these conditions.

Cross-reactive anti-galactocerebroside antibodies and Mycoplasma pneumoniae infections in the Guillain-Barré syndrome. (Article)

2002-09-01T00:00:00Z

Anti-galactocerebroside (GalC) antibodies are reported to be present in GBS patients with preceding Mycoplasma pneumoniae (MP) infection. We investigated the presence of anti-GalC reactivity in serum of a large group of GBS patients using ELISA and compared this with healthy controls and individuals with an uncomplicated MP infection. Anti-GalC antibody reactivity was present in 12% of the GBS patients. Furthermore, anti-GalC antibodies were associated with MP infections, a relatively mild form of the disease and demyelinating features. Anti-GalC antibodies cross-reacted with MP antigen. In conclusion, anti-GalC antibodies in GBS patients may be induced by molecular mimicry with MP.

Clinimetric evaluation of a new overall disability scale in immune mediated polyneuropathies (Article)

2002-01-01T00:00:00Z

OBJECTIVES: To determine the validity, reliability, and responsiveness of a new overall disability sum score in immune mediated polyneuropathies. METHODS: Three impairment measures (MRC sum score, sensory sum score, grip strength (Vigorimeter)) and three disability scales (an overall disability sum score (ODSS), Hughes' functional scale (f score), Rankin scale) were assessed in a cross sectional group of 113 clinically stable patients (83 with Guillain-Barre syndrome, 22 with chronic inflammatory demyelinating polyneuropathy (CIDP), eight with a gammopathy related polyneuropathy). The ODSS was also used serially in 20 patients with recently diagnosed Guillain-Barre syndrome (n = 7) or CIDP (n = 13) and changing clinical conditions. Multiple regression studies were performed to compare the impact of impairment disturbances (independent variables) on the various disability scales (dependent variable). RESULTS: Moderate to good construct validity (stable group: Spearman's rank test (absolute values), r = 0.41-0.79; longitudinal group: multiple correlation coefficient, R = 0.69-0.89; p < 0.006 for all associations) and reliability (intraclass correlation coefficient, R = 0.90-0.95; p < 0.0001) were demonstrated for the ODSS. Its SRM values were high (> 0.8), indicating good responsiveness. Impairment measures accounted for a higher variance proportion of the ODSS compared with the f score and Rankin (R = 0.64 v 0.56 and 0.45, respectively). CONCLUSIONS: All clinimetric requirements were met by the overall (arm and leg) disability sum score in immune mediated polyneuropathies. Its use is therefore suggested in evaluating immune mediated polyneuropathies.

Structure of Campylobacter jejuni lipopolysaccharides determines antiganglioside specificity and clinical features of Guillain-Barré and Miller Fisher patients (Article)

2002-01-01T00:00:00Z

Ganglioside mimicry in the lipopolysaccharide (LPS) fraction of Campylobacter jejuni isolated from Guillain-Barre syndrome (GBS) and Miller Fisher syndrome (MFS) patients was compared with isolates from patients with an uncomplicated enteritis. The antibody response to C. jejuni LPS and gangliosides in neuropathy patients and controls was compared as well. LPS from GBS and MFS-associated isolates more frequently contained ganglioside-like epitopes compared to control isolates. Almost all neuropathy patients showed a strong antibody response against LPS and multiple gangliosides in contrast to enteritis patients. Isolates from GBS patients more frequently had a GM1-like epitope than isolates from MFS patients. GQ1b-like epitopes were present in all MFS-associated isolates and was associated with anti-GQ1b antibody reactivity and the presence of oculomotor symptoms. These results demonstrate that the expression of ganglioside mimics is a risk factor for the development of post-Campylobacter neuropathy. This study provides additional evidence for the hypothesis that the LPS fraction determines the antiganglioside specificity and clinical features in post-Campylobacter neuropathy patients.

Prospective study on the relationship between infections and multiple sclerosis exacerbations (Article)

2002-01-01T00:00:00Z

One of the characteristics of multiple sclerosis is the unpredictable occurrence of exacerbations and remissions. These fluctuations in disease activity are related to alterations in (auto-)immune activity. Exacerbations lead to short-term morbidity, but may also influence long-term disability. This longitudinal study in 73 patients with relapsing-remitting multiple sclerosis assessed the contribution of systemic infections to the natural course of exacerbations. In addition, we analysed whether infections lead to an increase in the number of gadolinium-enhancing lesions. A total of 167 infections and 145 exacerbations were observed during 6466 patient weeks. During a predefined at-risk period (ARP) of 2 weeks before until 5 weeks after the onset of a clinical infection (predominantly upper airway infections), there was an increased risk of exacerbations (rate ratio 2.1), which is in accordance with previous studies. Exacerbations with onset during the ARP led more frequently to sustained deficit [increase of > or =1 Expanded Disability Status Scale (EDSS) point or > or =0.5 above EDSS 5.5 for >3 months] than exacerbations with onset outside the ARP, with a rate ratio of 3.8. Minor and major exacerbations were equally distributed between the ARP and non-ARP onset groups. ARP exacerbations were associated with significantly higher plasma levels of the inflammatory marker soluble intracellular adhesion molecule 1 than non-ARP exacerbations, indicating relatively enhanced immune activation during ARP relapses. Three serial MRI scans were performed after the onset of an infection over a 6-week period. There was no difference in the number of gadolinium-enhancing lesions between the three time points. In conclusion, exacerbations in the context of a systemic infection lead to more sustained damage than other exacerbations. There is no indication that this effect occurs through enhanced opening of the blood-brain barrier.

Ganglioside mimicry of Campylobacter jejuni lipopolysaccharides determines antiganglioside specificity in rabbits (Article)

2002-01-01T00:00:00Z

The core oligosaccharides of Campylobacter jejuni lipopolysaccharides (LPS) display molecular mimicry with gangliosides. Cross-reactive anti-LPS-antiganglioside antibodies have been implicated to show a crucial role in the pathogenesis of the Guillain-Barre and Miller Fisher syndrome. The specificity of the antiganglioside response is thought to depend on the oligosaccharide structure of the ganglioside mimic. To test this hypothesis and to investigate the potential of LPS from Campylobacter strains from enteritis patients to induce an antiganglioside response, we immunized rabbits with purified LPS from eight Campylobacter jejuni reference strains with biochemically well-defined distinct ganglioside mimics and determined the presence of antiganglioside antibodies. All rabbits produced immunoglobulin G (IgM) and IgG anti-LPS antibodies, and the specificity of the cross-reactive antiganglioside response indeed corresponded with the biochemically defined mimic. Most rabbits also had antibody reactivity against additional gangliosides, and there were slight differences in the fine specificity of the antibody response between rabbits that had been immunized with LPS from the same Campylobacter strain. High anti-LPS and antiganglioside titers persisted over a 10-month period. In conclusion, the structure of the LPS only partly determines the antiganglioside specificity. Other strain-specific as well as host-related factors influence the induction and fine-specificity of the cross-reactive anti-LPS-antiganglioside response.

Guillain-Barré syndrome- and Miller Fisher syndrome-associated Campylobacter jejuni lipopolysaccharides induce anti-GM1 and anti-GQ1b Antibodies in rabbits. (Article)

2001-04-05T00:00:00Z

Campylobacter jejuni infections are thought to induce antiganglioside antibodies in patients with Guillain-Barre syndrome (GBS) and Miller Fisher syndrome (MFS) by molecular mimicry between C. jejuni lipopolysaccharides (LPS) and gangliosides. We used purified LPS fractions from five Campylobacter strains to induce antiganglioside responses in rabbits. The animals that received injections with LPS from GBS-associated strains developed anti-GM1 and anti-GA1 antibodies. Animals injected with LPS from one MFS-related C. jejuni strain produced anti-GQ1b antibodies. Rabbits that were injected with Penner O:3 LPS had a strong anti-LPS response, but no antiganglioside reactivity was observed. The antiganglioside specificity in the rabbits reflected the specificity in the patients from whom the strains were isolated. In conclusion, our results indicate that an immune response against GBS- and MFS-associated C. jejuni LPS results in antiganglioside antibodies. These results provide strong support for molecular mimicry as a mechanism in the induction of antiganglioside antibodies following infections.

Reliability and responsiveness of a graduated tuning fork in immune mediated polyneuropathies. The Inflammatory Neuropathy Cause and Treatment (INCAT) Group (Article)

2000-01-01T00:00:00Z

The interobserver and intraobserver reliability of the Rydel-Seiffer (RS) graduated tuning fork was evaluated in 113 patients with a clinically stable immune mediated polyneuropathy (83 patients who had had Guillain-Barre syndrome (GBS) in the past, 22 with a chronic inflammatory demyelinating polyneuropathy (CIDP), and eight with a polyneuropathy associated with a gammopathy of undetermined significance). Additionally, the responsiveness of this instrument was serially investigated in 20 patients with recently diagnosed GBS or CIDP and changing clinical conditions. The measures were done in triplicate at eight different locations in the limbs and the values were compared with the recently published vibration threshold reference values. Good interobserver and intraobserver agreements (quadratic weighted kappa=0.67-0.98) and high responsiveness values (standardised response mean scores>0.8) were demonstrated for the RS tuning fork. These results provide, in addition to literature findings, further evidence for incorporation of this easily applicable instrument in routine neurological examination.

Chronic motor neuropathies: response to interferon-beta1a after failure of conventional therapies (Article)

1999-01-01T00:00:00Z

OBJECTIVES: The effect of interferon-beta1a (INF-beta1a; Rebif) was studied in patients with chronic motor neuropathies not improving after conventional treatments such as immunoglobulins, steroids, cyclophosphamide or plasma exchange. METHODS: A prospective open study was performed with a duration of 6-12 months. Three patients with a multifocal motor neuropathy and one patient with a pure motor form of chronic inflammatory demyelinating polyneuropathy were enrolled. Three patients had anti-GM1 antibodies. Treatment consisted of subcutaneous injections of IBF-beta1a (6 MIU), three times a week. Primary outcome was assessed at the level of disability using the nine hole peg test, the 10 metres walking test, and the modified Rankin scale. Secondary outcome was measured at the impairment level using a slightly modified MRC sumscore. RESULTS: All patients showed a significant improvement on the modified MRC sumscore. The time required to walk 10 metres and to fulfil the nine hole peg test was also significantly reduced in the first 3 months in most patients. However, the translation of these results to functional improvement on the modified Rankin was only seen in two patients. There were no severe adverse events. Motor conduction blocks were partially restored in one patient only. Anti-GM1 antibody titres did not change. CONCLUSION: These findings indicate that severely affected patients with chronic motor neuropathies not responding to conventional therapies may improve when treated with INF-beta1a. From this study it is suggested that INF-beta1a should be administered in patients with chronic motor neuropathies for a period of up to 3 months before deciding to cease treatment. A controlled trial is necessary to confirm these findings.

Risk factors for treatment related clinical fluctuations in Guillain-Barré syndrome. Dutch Guillain-Barré study group (Article)

1998-01-01T00:00:00Z

The risk factors for treatment related clinical fluctuations, relapses occurring after initial therapeutic induced stabilisation or improvement, were evaluated in a group of 172 patients with Guillain-Barre syndrome. Clinical, laboratory, and electrodiagnostic features of all 16 patients with Guillain-Barre syndrome with treatment related fluctuations, of whom 13 were retreated, were compared with those who did not have fluctuations. No significant differences were found between patients with Guillain-Barre syndrome treated with plasma exchange and patients treated with intravenous immune globulins either alone or in combination with high dose methylprednisolone. None of the patients with Guillain-Barre syndrome with preceding gastrointestinal illness, initial predominant distal weakness, acute motor neuropathy, or anti-GM1 antibodies showed treatment related fluctuations. On the other hand patients with fluctuations showed a trend to have the fluctuations after a protracted disease course. It is therefore suggested that treatment related clinical fluctuations are due to a more prolonged immune attack. There is no indication that the fluctuations are related to treatment modality. The results of this study may help the neurologist to identify patients with Guillain-Barre syndrome who are at risk for treatment related fluctuations.

Measuring vibration threshold with a graduated tuning fork in normal aging and in patients with polyneuropathy. European Inflammatory Neuropathy Cause and Treatment (INCAT) group (Article)

1998-01-01T00:00:00Z

OBJECTIVE: To provide clinically useful vibration threshold normal values. METHODS: The graduated Rydel-Seiffer tuning fork was evaluated in 198 healthy controls and 59 patients with a polyneuropathy. The measures were done in triplicate at four locations: the distal interphalangeal joint of the index finger, ulnar styloid process, interphalangeal joint of the hallux, and internal malleolus. The values obtained with this tuning fork in healthy controls and patients with polyneuropathy were compared with the values of an electronic device, the Vibrameter. RESULTS: Vibration sense was better perceived in the arms compared with the legs. There was a significant age related decline of vibration sense at all locations. The values from the Rydel-Seiffer tuning fork and the Vibrameter were significantly correlated in both groups. The sensitivity of these two instruments for the four sites examined in the polyneuropathy group ranged from 29-76% and 31-73%, respectively and was the highest at the hallux for both instruments. CONCLUSION: This study provides clinical useful normal values of vibration threshold for the Rydel-Seiffer tuning fork. This is a simple and easily applicable instrument that assesses vibration sense semiquantitatively and should therefore have a place in routine neurological examination.